Evaluation of the Safety of Adjunct Brexpiprazole in Elderly Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of the Safety of Adjunct Brexpiprazole in Elderly Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Treatment (NCT02400346), a na phase 3 study. The primary outcome is Number of Patients With Treatment-Emergent Adverse Events.

2. Clinical Question

The clinical question is primarily about safety and tolerability during the study period, not about estimating a treatment effect against a control. A treatment-emergent adverse event is defined in the registry as an adverse event that started or increased in intensity at or after the baseline visit. This definition concerns when an event arose or worsened; it does not by itself establish that study treatment caused the event.

The registry identifies 132 enrolled patients and reports adverse-event counts for the group receiving brexpiprazole plus ADT. It does not report a comparison group, an estimate of the difference between treatments, or a result for the primary endpoint count. Consequently, the question that can be addressed from these registry entries is descriptive: what adverse-event counts were recorded in this treated group, and how much can those counts establish without a control group?

3. Trial Design

This was a Phase 3 interventional study listed as completed. Its official description identifies it as open-label, flexible-dose, long-term, and designed to evaluate the safety and tolerability of brexpiprazole as adjunctive treatment in elderly patients with major depressive disorder and an inadequate response to antidepressant treatment. The registry lists enrollment of 132. The study began in 2015-03 and reached primary completion in 2016-06.

The design is recorded as single-group, with no allocation to separate study arms and no masking. All patients continued their current antidepressant treatment and received brexpiprazole in addition. Thus, the observed group represents the combination of adjunct brexpiprazole and ongoing ADT, rather than brexpiprazole used alone. The registry lists ADT as an intervention as well as adjunct brexpiprazole, but the arm description clarifies that ADT continued alongside brexpiprazole.

Open-label means that treatment assignment was not masked in the study design. In a single-group study, participants do not have a concurrent randomized control arm for comparison. The design can describe events observed among treated participants, but it cannot separate events associated with the study treatment from events that might have occurred with ongoing ADT, the underlying condition, or other circumstances. This is an important distinction when interpreting safety observations.

The primary outcome is the number of patients with treatment-emergent adverse events, with a timeframe from baseline to 30 weeks. The registry record lists one outcome measure and no statistical analyses. It does not report a detailed dose schedule, visit schedule, retention information, or a rationale for the enrollment target. Those details are not reported in the registry record.

The stated purpose is to evaluate safety and tolerability in an elderly population with inadequate response to antidepressant treatment. The design is consistent with a descriptive safety question in a group receiving adjunct treatment, but the information recorded does not support a controlled treatment comparison or a causal estimate of the effect attributable to brexpiprazole.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

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 Number of Patients With Treatment-Emergent Adverse Events, measured over Baseline to 30 weeks.

The primary endpoint is the number of patients with treatment-emergent adverse events from baseline to 30 weeks. Under the registry definition, an event qualifies as treatment-emergent if it begins or increases in intensity at or after the baseline visit. The endpoint is a participant count, rather than a measure of symptom improvement or a count of event episodes.

A participant-based endpoint can give a direct description of how many people had at least one event meeting the definition during the stated period. It is useful in safety monitoring because the occurrence of an adverse event in a person may matter even when the total number of event episodes is not the focus. It also avoids treating multiple events in one person as if they were events in separate people.

That count alone does not establish whether an event was caused by treatment, how severe it was, how long it lasted, or whether it led to a change in treatment. Those questions require additional definitions and data. The registry lists a primary outcome measure but does not report its result as a primary endpoint count in the information summarized for this analysis. The adverse-event counts elsewhere in the record should therefore be read as their own descriptive safety figures, not automatically treated as the reported primary endpoint result.

In general, a fixed observation window makes the endpoint interpretable only for that period and under the study’s event definition. Here, the window is baseline to 30 weeks; it does not describe safety outside that interval.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry is limited. It identifies the primary outcome as a participant count and gives adverse-event counts for one group, but it does not list statistical analyses. As a result, interpretation should focus on what the counts describe and avoid implying that an unreported model or test was used.

What does a participant count represent?

A participant count records how many people met a stated event definition during a stated period. For this study, the primary outcome is the number of patients with treatment-emergent adverse events from baseline to 30 weeks. A participant is counted for this type of endpoint if at least one qualifying event occurred; repeated episodes in the same person are not separate participants. This differs from an event count, which can count multiple episodes in one person.

The registry’s safety entries distinguish serious adverse events from other adverse events and report a count at risk for each category. These categories should be interpreted according to their registry labels. The registry entries do not establish that the categories are mutually exclusive, so their counts should not be added to construct a total. Nor should the death count be added to either adverse-event count: a death may be represented in a safety record in ways that overlap with other event reporting.

Why does the design matter for inference?

In general, a controlled comparison estimates how outcomes differ between groups under specified conditions. Random allocation can help balance measured and unmeasured factors between groups, while masking can reduce some influences on assessment and reporting. This study is listed as single-group, open-label, and without allocation to a control arm. It therefore supplies no concurrent treatment contrast. A count observed in one group cannot, by itself, estimate the difference that would have occurred under another treatment.

In general, a confidence interval communicates statistical uncertainty around an estimate under a chosen method and model. A hypothesis test evaluates data against a specified null hypothesis and analysis plan. Neither an interval nor a test is reported in the registry record for these outcomes. Their absence means that the posted counts should be read descriptively; it does not mean that a particular test was nonsignificant or that a treatment effect was absent.

What do the sample-size assumptions mean?

The registry describes a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a specified fraction of the observed effect. These are assumptions for a hypothetical planning calculation, not a description of the actual single-group study design. The illustration is not evidence that the trial was designed with those assumptions, and it is not observed power. The registry does not report the trial’s own sample-size justification.

In general, sample-size planning asks what amount of information might be needed to detect an effect under stated assumptions. Such calculations depend on the effect size, variability or event frequency, allocation, significance level, and statistical method. If those assumptions do not match the design or the actual data, the planning output does not describe the precision of the observed trial result. The record’s two-arm planning assumptions should not be confused with the one-group treatment experience reported for this study.

For count outcomes, the analysis method must also match the target quantity. A participant-based binary endpoint and a count of recurrent event episodes are not interchangeable. In general, event-count analyses may need to account for over-dispersion, which occurs when variation in counts exceeds what a simple model assumes. This study’s primary endpoint is defined as a number of participants, and the registry does not report a recurrent-event model or an over-dispersion adjustment. No such method should be inferred.

What does the record leave unresolved?

The registry record does not report confidence intervals, p-values, adjusted analyses, a statistical analysis plan, handling of missing outcome data, or a defined analysis population. It also does not report whether interim analyses were conducted. These omissions limit assessment of the precision, robustness, and prespecification of any analysis. In general, a prespecified analysis plan helps readers understand which outcomes, populations, and methods were selected before results were examined; without a reported plan, those details cannot be verified from this record.

The listed enrollment does not, on its own, establish how many participants contributed evaluable data to every outcome. In general, missing observations can affect a safety count if participants are not observed for the same length of time or if event status is unknown. The registry information does not describe such follow-up or missingness patterns. The most defensible interpretation is therefore limited to the recorded counts and definitions, without a reconstructed estimate or an assumption about unreported analysis choices.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Adjunct Brexpiprazole")
n      <- c(132)
events <- c(102)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Adjunct Brexpiprazole  132  102  77.3  69.2  84.1  69.4  83.6  69.4  83.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary outcome measure and no statistical analyses. It does not report a statistical analysis plan, a hierarchy of outcomes, or a multiplicity adjustment. Thus, it is not possible to determine whether any formal hypothesis tests were planned, whether additional outcomes were tested, or how multiple comparisons might have been handled. No claim about statistical significance or the control of false-positive findings can be made from the information recorded.

In general, multiplicity arises when several hypotheses or outcomes are tested. Testing many questions can increase the chance of at least one apparently unusual result by chance alone. A prespecified hierarchy or adjustment can address that concern, depending on the study’s aims. Those are general statistical considerations; the registry does not report which, if any, applied to this study.

Missing-data methods and analysis populations are also not reported in the registry record. It does not specify how participants with incomplete follow-up, early discontinuation, or unavailable event information were handled, nor does it define an analysis population for the primary endpoint. The enrollment figure is not enough to infer that every enrolled participant contributed complete data through the full timeframe.

These gaps matter because safety interpretation depends on the observation period and on whether event status is known for participants who discontinue or miss visits. In general, excluding participants with incomplete information can alter a descriptive count if their event experience differs from that of participants with complete follow-up. The record does not provide enough information to assess that possibility or to reproduce an analysis.

The appropriate reading is therefore descriptive and bounded: the registry records the stated adverse-event counts and the primary endpoint definition, but it does not document the inferential procedures or missing-data rules needed for a fuller analysis.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute myocardial infarction (0.8%), myocardial rupture (0.8%), postoperative wound infection (0.8%), eye contusion (0.8%), facial bones fracture (0.8%).

The registry lists 6 patients with serious adverse events among 132 at risk in the brexpiprazole-plus-ADT group. It lists 79 patients with other adverse events among 132 at risk, along with 1 death. These figures are counts for one group, not comparative estimates. They should be read as recorded safety observations during the study, not as evidence that treatment caused or prevented the events.

The serious-event terms listed are acute myocardial infarction, myocardial rupture, postoperative wound infection, eye contusion, facial bones fracture, and fall. Each term is reported as 0.8%. The record does not give further details in the information about event timing, severity beyond the serious classification, treatment relatedness, or participant-level overlap. The same participant may have had more than one event, so term entries should not be treated as separate people or added together.

The death count is reported separately. The registry information does not establish the cause of death or its relationship to treatment. Likewise, the label other adverse events should not be taken to mean that each event was non-serious unless that classification is explicitly established. The counts do not reveal how long each participant was observed, whether follow-up was complete, or how events were collected after treatment discontinuation.

These figures describe the safety reporting in this group; without a concurrent control group, they do not establish a relative risk or comparative safety profile.

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

The result that can be read directly from the registry is a set of safety counts in a single group receiving adjunct brexpiprazole while continuing ADT. The record lists 6 patients with serious adverse events, 79 with other adverse events, and 1 death. It also lists six serious-event terms, each reported as 0.8%. These observations describe what the registry records for the study group; they are not estimates of how outcomes compare with another treatment.

The primary outcome is defined as the number of patients with treatment-emergent adverse events from baseline to 30 weeks. The registry record does not report a result for that primary endpoint count. The other adverse-event count should not be assumed to be the primary endpoint result because the record does not establish that the category, definition, and timeframe are identical. Nor does the absence of a reported primary endpoint count mean that no such events occurred.

The design cannot establish causation. In a single-group study, observed events can arise from many sources, including the underlying condition, ongoing ADT, other circumstances, or study treatment. Without a concurrent control group, the data do not show what event counts would have occurred under a different treatment strategy. Open-label conduct also means treatment was not masked, which can influence reporting or assessment in general.

The record does not report a confidence interval or a statistical test for the safety counts. Accordingly, it does not quantify uncertainty around a comparative effect, and it does not support a conclusion that the treatment is safer or less safe than an alternative. A descriptive count can be important for characterizing observed experience while remaining limited as evidence of a treatment effect.

The study’s scope is also bounded by its stated timeframe, population, and regimen: elderly patients with major depressive disorder and inadequate response to antidepressant treatment, receiving adjunct brexpiprazole with continued ADT, with the primary endpoint window running from baseline to 30 weeks. The registry information does not establish how results would generalize beyond that setting or period.

14. Why This Trial Matters Statistically

This study matters statistically because it illustrates the difference between describing safety events and estimating a comparative treatment effect. A single-group study can record the number of patients experiencing events during treatment. It cannot, without a concurrent comparator, determine how those counts differ from what would have occurred under another treatment strategy.

The distinction is especially important for adverse events. An event occurring after baseline meets the registry’s treatment-emergent timing definition, but temporal order alone does not establish that treatment caused it. A control group and a prespecified comparative analysis can help address the counterfactual question of what might have happened without the adjunct treatment. The design recorded does not provide that comparison.

The record also shows why endpoint definitions and reported results must be kept distinct. The primary endpoint is a participant count for treatment-emergent adverse events over baseline to 30 weeks, while the listed safety summary provides separate serious and other adverse-event counts. Because the primary endpoint result is not reported in the registry record, the related safety counts should not be substituted for it without evidence that the definitions match.

Finally, the registry’s two-arm sample-size planning assumptions are not the same as the actual single-group design. Planning calculations depend on assumptions and do not become evidence about observed precision or treatment effect. The study therefore offers useful descriptive safety information, while also demonstrating why design, endpoint reporting, and analysis details determine which statistical conclusions are justified.

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 main limitation is the single-group design. There is no concurrent control group, so the observed adverse-event counts cannot be compared directly with outcomes under ADT alone or another treatment. The study is also open-label, and the registry lists no masking. These features restrict causal interpretation and may affect event reporting or assessment in general.

The registry does not report the primary endpoint result, even though it defines the endpoint as the number of patients with treatment-emergent adverse events from baseline to 30 weeks. It does provide separate serious and other adverse-event counts, but the record does not establish that the other-event count is equivalent to the primary endpoint. No unreported result can be reconstructed from the available counts.

Further details needed to assess safety reporting are not reported in the registry record. These include participant-level overlap across event categories, event timing and duration, treatment relatedness, follow-up completeness, withdrawals, and how missing event information was handled. The record also does not report an analysis population or statistical analysis plan, confidence intervals, or inferential tests.

Generalizability is limited to the study’s stated setting and population: elderly patients with major depressive disorder and an inadequate response to antidepressant treatment receiving adjunct brexpiprazole while continuing ADT. The registry information does not specify additional population characteristics or establish whether the recorded experience applies outside the baseline-to-30-weeks primary endpoint timeframe. These limitations favor a descriptive interpretation rather than a broad or comparative conclusion.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Evaluation of the Safety of Adjunct Brexpiprazole in Elderly Patients With Major Depressive Disorder and an Inadequate Response to Antidepressant Treatment — NCT02400346.
• Registry record last updated 2017-08-10; status last verified 2017-07.
• Results first posted 2017-06-26.
• 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 NCT02400346, a completed Phase 3, open-label, flexible-dose, single-group study sponsored by H. Lundbeck A/S. It enrolled 132 elderly patients with major depressive disorder and an inadequate response to antidepressant treatment. The study began in 2015-03 and reached primary completion in 2016-06.

All patients continued their current ADT and received adjunct brexpiprazole. The primary endpoint was the number of patients with treatment-emergent adverse events from baseline to 30 weeks. The registry lists 6 patients with serious adverse events, 79 with other adverse events, and 1 death in the treatment group; it does not report the primary endpoint result or statistical analyses.

Because there was no concurrent control group, these counts describe recorded events in the treated group and do not establish comparative safety or causation. Analysis methods, missing-data handling, and the trial’s own sample-size justification are not reported in the registry record.