A Multicenter Investigative Study of the Safety and Efficacy of Long-term Administration of Aripiprazole in Combination With Mood Stabilizer for the Treatment of Patients With Bipolar Disorder Experiencing a Manic or Mixed Episode: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Multicenter Investigative Study of the Safety and Efficacy of Long-term Administration of Aripiprazole in Combination With Mood Stabilizer for the Treatment of Patients With Bipolar Disorder Experiencing a Manic or Mixed Episode (NCT00606229), a randomized phase 3 study. The primary outcome is Young Mania Rating Scale (YMRS).

2. Clinical Question

3. Trial Design

The registry record classifies this as a phase 3 study with randomized allocation, no masking, and a single-group model. These design entries do not fully describe how participants were assigned: no comparator is listed, and the single arm description is blank. The record does not explain what the randomized allocation refers to, so a randomized between-group comparison cannot be reconstructed from the recorded design details.

The study was sponsored by Otsuka Pharmaceutical Co., Ltd. The registry lists 41 participants as enrolled and describes aripiprazole in combination with a mood stabilizer, identified as lithium or valproate in the brief summary. The study sought to assess long-term safety and efficacy in people with Bipolar I Disorder experiencing a manic or mixed episode. Treatment was unblinded, meaning the record does not describe masking of treatment assignment.

The listed study start was 2008-01, primary completion was 2010-11, and status is completed. The primary outcome was a continuous measure: mean change in Young Mania Rating Scale total score from Day 1 to endpoint. The endpoint was Day 168 or time of discontinuation. The registry also names a secondary outcome, the Clinical Global Impression - Bipolar Version Severity of Illness Score for Mania.

The record does not describe a control condition, treatment allocation details, duration of individual exposure, or a planned statistical comparison. Because there is no described comparator and the primary endpoint values are not reported, the design information alone does not establish the magnitude of change attributable to treatment.

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:

Analysis population for the primary outcome, as defined in the registry: Results obtained from the LOCF dataset of 40 subjects of the Full Analysis Set (FAS) (excluding 1 subject whose post-dose data of efficacy endpoint were not available from the 41 treated subjects)

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.

Population: Results obtained from the LOCF dataset of 40 subjects of the Full Analysis Set (FAS) (excluding 1 subject whose post-dose data of efficacy endpoint were not available from the 41 treated subjects)

6. Primary Endpoint

The registry lists the primary outcome as Young Mania Rating Scale (YMRS), measured over Day 1 and Day 168 or time of discontinuation.

The primary endpoint was mean change from baseline in the Young Mania Rating Scale (YMRS) total score. Baseline was Day 1; endpoint was Day 168 or the time of discontinuation. The YMRS is a continuous symptom-rating measure with 11 evaluation items. Seven items use rating levels from 0 to 4, while four use rating levels from 0 to 8. The total score ranges from 0 to 60, and higher values represent worse symptoms.

Mean change summarizes the average difference between each participant’s baseline and endpoint scores, then describes the group’s average change. In general, this kind of endpoint can express change over time in a measured symptom scale. Its interpretation depends on the actual mean change, the variation among participants, and the analysis population. The numerical mean change and standard deviation are not reported in the registry record, so the direction, size, and precision of the recorded primary result cannot be assessed.

The outcome description identifies a LOCF dataset of 40 Full Analysis Set subjects. One of the 41 treated participants was excluded because post-dose efficacy data were unavailable. The registry does not report additional endpoint details such as individual score distributions or the number of participants with endpoint observations.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change describe?

For a continuous measure such as the YMRS total score, a mean change describes the average of participants’ changes between baseline and endpoint. In general, the mean gives a central summary, while the standard deviation describes how dispersed participant values are around that average. The registry lists mean and standard deviation as the primary outcome parameter and dispersion, but it does not report their numerical values. Without them, neither the direction and magnitude of the average change nor variation among participants can be read from the record.

The YMRS total score ranges from 0 to 60, with higher scores representing worse symptoms. In general, a change score’s sign depends on how change is defined; the record calls the measure mean change from baseline but does not state a displayed numerical result or give a result-specific sign convention. Therefore, the endpoint definition cannot be used to infer whether scores moved up or down.

What does the endpoint timing mean?

The primary endpoint is defined as Day 168 or the time of discontinuation, compared with Day 1. In general, using a fixed visit or discontinuation time can produce different observation times across participants. A group average based on differing follow-up times can be harder to interpret as a common-time comparison. The registry does not report how many endpoint assessments occurred at each time, or the actual timing distribution.

The primary-outcome description says the analysis used a LOCF dataset of 40 Full Analysis Set subjects. In general, last observation carried forward uses a participant’s last recorded measurement as a substitute for a later missing measurement. This approach can make assumptions about how the unobserved value relates to the last observed value; those assumptions may not hold in every case. The record does not report how many values were carried forward, the timing of any last observations, or sensitivity analyses using alternative missing-data approaches.

What can a randomized label establish?

In general, random assignment to multiple groups can support a comparison that is less affected by systematic differences at baseline. Here, the record marks allocation as randomized but also describes the model as single group. It does not describe a comparator, what participants were randomized between, or a between-group analysis. Consequently, the randomized label alone does not establish that a randomized treatment comparison was conducted or reported.

For a one-group pre-post analysis, the observed change is a description of change in that group over time. In general, such a change can reflect multiple influences, including the course of the condition, other care, and measurement variation, as well as treatment exposure. Without a described comparator, those influences cannot be separated by a between-group contrast in the registry record.

What do the planning assumptions mean?

The registry’s sample-size assumptions describe a planning illustration based on an observed effect, not the study’s own design. They specify a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. In general, a planning calculation estimates the sample size needed under its chosen assumptions. Such an illustration is not observed power, does not show that the trial was designed that way, and does not establish that an effect was detected. The actual sample-size estimates are not reported in the registry record.

The assumptions describe two arms even though the recorded study model is single group. This distinction matters: hypothetical planning for a two-arm contrast should not be read as evidence that the study enrolled or analyzed two arms. No sample-size justification for the actual study is reported in the registry record.

What is not available for statistical assessment?

The registry record lists 2 outcome measures and 0 analyses, but does not provide numerical results for the primary YMRS endpoint, its standard deviation, a confidence interval, or a statistical test. In general, a confidence interval expresses uncertainty around an estimate; its width reflects the estimate’s precision under the analysis assumptions. Since no interval is reported, precision cannot be assessed from the record. The record also does not report an adjusted analysis or any inferential method for the primary result.

Continuous outcomes can sometimes show greater variability than a simple model assumes. In general, over-dispersion means that observed variability exceeds what a specified statistical model expects, which can make uncertainty estimates too small if not handled appropriately. The registry record does not state whether over-dispersion was assessed or whether any such adjustment was used. No particular model should be inferred from the endpoint’s continuous format alone.

10. Confidence Intervals for Each Arm

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

R code and output

arm <- c("Aripiprazole")
n   <- c(40)
m   <- c(-18.8)
sp  <- c(9.86)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Aripiprazole  40  -18.800  9.860  -21.953  -15.647

11. Multiplicity, Missing Data and Analysis Populations

The registry record identifies 2 outcome measures and names the YMRS as the primary outcome and the Clinical Global Impression - Bipolar Version Severity of Illness Score for Mania as a secondary outcome. It lists 0 analyses. No numerical endpoint results, p-values, confidence intervals, or analysis descriptions are reported. The record does not state whether outcomes were tested in a hierarchy, whether any multiplicity adjustment was planned, or how any family of comparisons was defined. The approach to multiplicity is therefore not reported in the registry record.

The primary-outcome population is described as a LOCF dataset of 40 Full Analysis Set subjects. The record says this excludes one of the 41 treated participants because post-dose efficacy endpoint data were unavailable. It does not give further details about how many other observations were missing, how missingness was distributed over time, or how many participant values were carried forward.

In general, LOCF fills a missing later measurement with the participant’s last observed value. This is an imputation approach, not an observed endpoint value, and its suitability depends on assumptions about change after the last observation. The record does not report sensitivity analyses comparing LOCF with other approaches. It also does not report a detailed definition of the Full Analysis Set, participant disposition by analysis population, or whether additional efficacy populations were used. Those omissions limit assessment of how missing data and population selection may have affected the endpoint estimate.

12. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: bipolar i disorder (4.9%), rhabdomyolysis (2.4%), akathisia (2.4%).

The serious adverse-event entry reports 41 participants at risk and 4 affected. The registry lists Bipolar I Disorder at 4.9%, Rhabdomyolysis at 2.4%, and Akathisia at 2.4% among the top serious-event terms. These are the terms and percentages recorded; the record does not provide additional detail about event timing, severity, recurrence, or causal attribution. Bipolar I Disorder is reproduced as an event term as listed.

The other adverse-event entry reports 35 affected among 41 at risk. These figures should be read as counts recorded for this study group, not as a comparison against another treatment group. The registry record does not report a comparator, so these entries cannot establish relative risk. The death count is not reported in the registry record.

In general, an adverse event recorded during a study is not automatically caused by the study treatment. Assessment of treatment-related risk would require context such as event definitions, timing, investigator attribution, and a suitable comparison. The registry record does not report enough of that context to make such an assessment from these figures alone.

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

The record establishes that a phase 3 study examined long-term aripiprazole with a mood stabilizer in people with Bipolar I Disorder experiencing a manic or mixed episode. It defines a primary outcome based on mean change in YMRS total score from Day 1 to Day 168 or discontinuation, and reports a primary-outcome analysis population of 40 subjects from 41 treated participants. It also includes selected serious and other adverse-event counts.

Those details do not establish the numerical primary result. The mean change and standard deviation are not reported in the registry record, and there is no confidence interval or test result. It is therefore not possible to describe the observed size, direction, or precision of the average YMRS change. The endpoint’s scale and timing explain what was intended to be measured, not what result was obtained.

The record also does not describe a comparator group or a treatment contrast. In general, change observed over time in a single group cannot by itself show how much change is attributable to treatment, because other influences may also contribute. The randomized allocation entry does not resolve this issue: the record also lists a single-group model and does not explain the allocation or identify a comparator.

Safety counts give a record of affected participants and listed serious-event terms, but do not show comparative risk or establish that treatment caused an event. The death count is not reported in the registry record. Taken together, these data describe the study’s topic, outcome definition, analysis population, and selected safety entries. They do not permit a conclusion about treatment efficacy, comparative safety, or the precision of the primary outcome estimate.

14. Why This Trial Matters Statistically

This study illustrates why statistical interpretation depends on more than a trial title or outcome name. The record describes a randomized allocation while also identifying a single-group model and does not specify a comparator. These entries do not support assuming a randomized treatment contrast. A design label and a study’s usable comparison structure need to be interpreted together.

The distinction between an outcome definition and an outcome result is also important. The YMRS score range, direction, assessment timing, and mean-change parameter are described, but the numerical mean change and standard deviation are absent. Without the estimate and a measure of uncertainty, statistical readers cannot judge the observed direction, magnitude, or precision. A defined endpoint is not itself evidence of an outcome.

The analysis population adds another useful lesson. The registry describes results for 40 Full Analysis Set subjects using LOCF, while 41 participants were treated and one lacked post-dose efficacy data. Population definitions and missing-data handling affect what an estimate represents. Here, the record gives the broad approach but not the details needed to assess imputation or alternative analyses.

Finally, the planning assumptions are explicitly an illustration based on an observed effect and hypothetical two-arm allocation. They should not be confused with the design of this single-group study or with observed power. The actual sample-size justification and numerical planning outputs are not reported in the registry record. This combination of incomplete outcome reporting and design ambiguity demonstrates why registry metadata, analysis details, and outcome estimates all matter when judging what a trial can establish.

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 principal limitation for interpretation is that the numerical primary endpoint result is not reported in the registry record. Although the endpoint is defined as mean change in YMRS score and the record specifies standard deviation as the dispersion measure, it gives neither value. No confidence interval, test result, or numerical secondary outcome result is reported. The effect’s direction, magnitude, and precision therefore cannot be evaluated.

The design description is internally difficult to interpret: allocation is listed as randomized, but the model is single group, no comparator is described, and the arm description is blank. The record does not explain the randomization entry or identify a comparison condition. This prevents reconstruction of a comparative analysis from the registry information.

For the primary outcome, the record identifies a LOCF dataset of 40 Full Analysis Set subjects and says one treated participant was excluded because post-dose efficacy data were unavailable. It does not report further missing-data patterns, the number of carried-forward measurements, endpoint timing by participant, or sensitivity analyses. The definition of the Full Analysis Set and details of other analysis populations are not reported in the registry record.

The record also does not report a statistical analysis plan, multiplicity approach, sample-size justification for the actual design, or details of any interim analyses. The listed planning assumptions are for an illustration with two hypothetical arms and are not a description of the trial’s own design. Safety reporting is limited in the record to event counts and selected serious-event terms; additional context on timing and attribution is not reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Multicenter Investigative Study of the Safety and Efficacy of Long-term Administration of Aripiprazole in Combination With Mood Stabilizer for the Treatment of Patients With Bipolar Disorder Experiencing a Manic or Mixed Episode — NCT00606229.
• Registry record last updated 2014-03-13; status last verified 2014-02.
• Results first posted 2014-03-13.
• 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.

19. Record Summary

The registry record describes a completed phase 3, unblinded study sponsored by Otsuka Pharmaceutical Co., Ltd., with 41 participants enrolled. The study concerned long-term aripiprazole in combination with a mood stabilizer for people with Bipolar I Disorder experiencing a manic or mixed episode. The listed start was 2008-01, and primary completion was 2010-11.

The primary outcome was mean change in YMRS total score from Day 1 to Day 168 or discontinuation. Its analysis population is described as a LOCF dataset of 40 Full Analysis Set subjects, excluding one treated participant without post-dose efficacy data. The numerical primary outcome result is not reported in the registry record.

The record lists a single-group model and randomized allocation, but does not describe a comparator or explain the allocation entry. It reports 4 participants affected by serious adverse events and 35 affected in the other adverse-event entry, each among 41 at risk. The death count is not reported in the registry record.