Long-term Safety and Tolerability of Cariprazine for Bipolar I Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Long-term Safety and Tolerability of Cariprazine for Bipolar I Disorder (NCT01059539), a na phase 3 study. The primary outcome is Change From Baseline in the YMRS Total Score at Week 16.

2. Clinical Question

3. Trial Design

This is a Phase 3, completed, long-term open-label study of cariprazine in participants with bipolar I disorder. The registry lists enrollment as 403 and identifies the study model as single-group. Allocation is listed as not applicable, and masking as none. Thus the design, as recorded, has no randomized control arm and participants and study personnel were not masked to treatment.

The intervention description names cariprazine. The arm is described as cariprazine 3–12 mg/day for 16 weeks. The dose schedule starts with 1.5 mg orally on Day 1 and 3.0 mg orally on Days 2 and 3. Starting on Day 4, the dose could be increased in increments of 3 mg every 2 days, up to a maximum of 12 mg, if response was not adequate and there were no tolerability issues. The registry arm description ends mid-sentence, so further details of the decision process are not reported in the registry record.

The study objective includes long-term safety, tolerability, and pharmacokinetics. The listed primary outcome is change from baseline in YMRS total score at Week 16. A listed secondary outcome is change from baseline in MADRS total score at Week 16. Although the record indicates two outcome measures, it reports no analyses. The numerical outcome results and the number of participants contributing to the outcome analyses are not reported in the registry record.

The study start date is 2010-02-28, and the primary completion date is 2012-02-29; its status is completed. These dates describe the registered study timeline, not the time at which any individual participant was followed. The record does not report a more detailed schedule of visits or follow-up beyond the stated Week 16 outcome timeframe.

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: Intent-to-treat population: All enrolled participants who took at least 1 dose of investigational product and who had a Baseline and at least 1 post-baseline assessment of the Young Mania Rating Scale.

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: Safety population: All enrolled participants who took at least 1 dose of investigational product.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in the YMRS Total Score at Week 16, measured over Baseline to Week 16.

The primary endpoint is change from baseline in the Young Mania Rating Scale (YMRS) total score at Week 16. The YMRS is an 11-item measure of manic symptoms, drawing on the participant’s perception of their condition over the previous 48 hours and the physician’s clinical observations during the interview. Its items cover areas including mood, activity and energy, sleep, irritability, speech, thought, behavior, appearance, and insight.

Each item is rated on a 5-point or 9-point scale, and the total can range from 0 to 60. Higher scores indicate worse manic symptoms. A negative change score indicates improvement, so the direction of a change is interpretable against the scale’s stated meaning. The endpoint is used to quantify change in manic symptoms over the study period rather than to record a simple event count.

In general, a continuous score can retain information about the degree of change across participants, rather than reducing each participant’s result to a yes-or-no category. Interpretation depends on the observed mean change, its variability, and the number of observations contributing to the analysis. The registry identifies the outcome as a mean with standard deviation, but does not report the mean change, standard deviation, or an uncertainty interval. The direction and size of the study’s YMRS result therefore cannot be determined from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry classifies the primary outcome as continuous and reports the intended summary as a mean with standard deviation. These describe different features of a distribution. In general, the mean is a measure of its central location, while the standard deviation describes how dispersed individual measurements are around that mean. Neither alone describes the uncertainty in the estimated mean; that typically requires an uncertainty measure such as a confidence interval. The primary result and its variability are not reported in the registry record.

What does change from baseline represent?

For this endpoint, change is the Week 16 score compared with the baseline score. The scale description sets the direction: a negative change score indicates improvement, while higher YMRS scores indicate worse manic symptoms. This definition tells a reader how to interpret the sign of a reported change, but it does not indicate what change was actually observed. The registry does not report the mean change or its standard deviation.

In general, a within-group change summarizes how scores differ over time among participants with measurements. It is not, by itself, a randomized estimate of the difference between treatment and control. A controlled comparison would require an appropriate comparator and an analysis contrasting groups. The record identifies a single-group design and no comparator, so the primary endpoint should be understood as a planned measure of change in that group, not as a between-group treatment contrast.

Why does the standard deviation matter?

In general, a standard deviation helps describe whether participant scores are clustered relatively closely around the mean or spread more widely. A mean change alone can hide substantial variation in individual outcomes. The standard deviation is not a confidence interval and does not directly show the precision of the estimated mean. Precision also depends on the amount of usable information and the analysis method. The registry specifies standard deviation as the dispersion measure but reports no numerical value for it.

For a confidence interval, the general interpretation is a range of values compatible with the data and the method used to construct the interval. A narrower interval indicates greater precision under that method; a wider interval indicates less precision. No confidence interval is reported for the primary or secondary outcome in the registry record. It is therefore not possible to use interval width to assess how precisely either outcome was estimated.

What can the design establish?

In general, randomization helps make treatment groups comparable with respect to measured and unmeasured characteristics at the start of a study. This trial is recorded as single-group, with allocation not applicable; it therefore does not have a randomized comparison in the registry record. Open-label means masking is listed as none. Without a control group, changes during follow-up cannot be interpreted as a treatment-versus-control difference. The design can describe outcomes observed in the study group if those results are reported, but the registry does not report the primary outcome result.

The registry states an intent-to-treat population definition for the primary endpoint: all enrolled participants who took at least one dose and had a baseline and at least one post-baseline YMRS assessment. This is a defined analysis population, but it is not equivalent to every enrolled participant regardless of data availability. The number who met the definition and the number included in the analysis are not reported in the registry record.

How should the planning illustration be read?

The registry describes a planning illustration based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It characterizes the effect to detect as a stated fraction of the observed effect. Such calculations are hypothetical planning exercises, not observed power and not a report of the trial’s actual design. The trial itself is single-group, so the two-arm assumptions do not describe its registered allocation. No numerical planning estimates are included in the registry record.

In general, a sample-size calculation depends on assumptions about the outcome, variability, effect to detect, significance level, allocation, and analysis method. Different assumptions can lead to different planning requirements. A calculation based on an observed effect is especially dependent on that effect estimate; it should not be read as proof that a future study would reproduce it. Since this registry record does not report the outcome estimate, it does not enable independent evaluation of the effect assumption behind the illustration.

Over-dispersion is a general concern when outcome variation is greater than a statistical model assumes: standard errors may then be underestimated if the model fails to account for the extra variability. The registry describes the primary endpoint as a continuous mean and standard deviation, but does not report a model, diagnostics, or an over-dispersion assessment. No particular issue with over-dispersion can therefore be inferred for this outcome.

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("Cariprazine 3-12 mg/Day for 16 Weeks")
n   <- c(399)
m   <- c(-15.2)
sp  <- c(9.2)
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  Cariprazine 3-12 mg/Day for 16 Weeks  399  -15.200  9.200  -16.105  -14.295

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary YMRS change outcome and a secondary MADRS change outcome, both at Week 16. When more than one outcome or analysis is considered, the chance of at least one apparently notable result can increase. In general, multiplicity procedures can be used to control that risk, but the appropriate approach depends on the planned testing strategy. A multiplicity adjustment or testing hierarchy is not reported in the registry record.

The record indicates two outcome measures and zero analyses. Numerical results, p-values, confidence intervals, and analysis-specific participant counts are not reported. The absence of a recorded analysis means it is not possible to assess whether any outcome was statistically distinguishable from no change, nor whether results were adjusted for multiple outcomes.

The primary outcome population is defined as enrolled participants who took at least one dose and had both a baseline and at least one post-baseline YMRS assessment. The record does not report how many participants met this definition or how many had a Week 16 measurement. It also does not explain how missing Week 16 scores were handled, whether any imputation was used, or whether a sensitivity analysis assessed the effect of missing data. Those analysis details are not reported in the registry record.

In general, missing outcome data can affect both the estimated average and its precision, particularly if participants without measurements differ systematically from those with measurements. The stated population definition requires some post-baseline data but does not, on its own, describe how an unavailable Week 16 value was addressed. The registry record does not provide enough information to assess the direction or possible impact of missingness.

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: mania (2.2%), depression (1.2%), akathisia (0.7%), suicidal ideation (0.5%), suicide attempt (0.5%).

The registry reports 34 serious adverse events among 402 at risk in the cariprazine group, 293 other adverse events among 402 at risk, and 0 deaths. It also lists serious-event terms with percentages: Mania, 2.2%; Depression, 1.2%; Akathisia, 0.7%; Suicidal ideation, 0.5%; Suicide attempt, 0.5%; and Angina pectoris, 0.2%. These figures describe the safety information recorded for this study group.

These are not comparisons against a control group. The study is single-group and open-label, so the registry supplies no randomized control event counts for estimating a relative difference. The figures should be read as descriptive records, not as evidence that an event was caused by or prevented by cariprazine. The record does not report additional event definitions or details about how the percentages were derived.

Serious adverse events and other adverse events are reported in separate categories. They should not be combined or treated as interchangeable measures. The count of 0 deaths is the registry’s reported value for this group; it does not supply a comparative estimate. These figures do not establish the absence of other risks or describe safety beyond the study’s reported period.

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

The study was designed to evaluate long-term safety, tolerability, and pharmacokinetics of cariprazine in participants with bipolar I disorder. Its registered primary symptom outcome was change in YMRS total score from baseline to Week 16. The scale definition gives a clear interpretation for a future reported change: negative change indicates improvement, and higher total scores indicate worse manic symptoms. However, no numerical YMRS result is reported in the registry record.

That absence matters. Without the mean change and its variability, the result’s magnitude cannot be described, and its precision cannot be judged. No confidence interval or p-value is reported. The same limitation applies to the listed secondary MADRS change outcome. The registry’s indication of two outcome measures and zero analyses is not evidence that the measures showed no change; it means the registry record does not report numerical analyses from which to determine what happened.

The safety counts offer descriptive information for the registered cariprazine group, including serious events, other events, and deaths. They do not establish a causal relationship between treatment and an event. With no randomized control group, event frequencies cannot be contrasted with an alternative treatment or with a control condition in this record.

In general, an open-label, single-group study can document observations made during treatment, but it cannot by itself distinguish those observations from changes that might have occurred for other reasons. The design therefore does not support a controlled treatment-effect estimate. The posted record is informative about the study’s setup, the outcome definitions, and the adverse-event figures, but not about the size or precision of change in the primary symptom measure.

The findings should not be interpreted as showing either that treatment was effective or that it was ineffective. The registry record lacks the numerical outcome analyses needed to support either statement. Likewise, reported adverse-event counts alone do not establish comparative safety. The scope of interpretation is limited to what the record describes: one open-label group, the specified study period, and the outcomes and safety figures entered in the registry.

14. Why This Trial Matters Statistically

This trial is statistically notable for the contrast between its stated primary symptom outcome and its single-group design. A mean change in YMRS can describe how scores changed among participants with measurements, but without a randomized comparator it does not estimate a treatment-versus-control difference. Recognizing that distinction prevents a within-group measure from being overinterpreted as a causal effect.

The record also illustrates why an outcome definition is not the same as an outcome result. It specifies the scale, direction, population definition, and Week 16 timeframe, but does not report the mean change or its variability. Those missing quantities are essential for evaluating the size and precision of the measured change. A precise endpoint description cannot substitute for an analysis.

Safety counts are similarly dependent on context. The registry reports event counts for the cariprazine group, but does not provide a randomized control group for comparison. The figures can describe what was recorded in the group; they cannot, by themselves, quantify a comparative risk or establish causation.

Finally, the registry indicates two outcome measures and zero analyses, while offering no reported multiplicity or missing-data methods. Those omissions make it difficult to evaluate how the planned outcomes were analyzed or how incomplete measurements may have affected conclusions. The case underscores a central statistical principle: interpretation depends not only on which measures were planned, but also on the results, analysis population, uncertainty, and design that produced them.

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.

A key limitation is that the registry record does not report numerical results for the primary YMRS endpoint or the listed secondary MADRS endpoint. It therefore does not allow assessment of the observed mean change, variability, or precision. Although the record indicates two outcome measures, it reports zero analyses. The number of participants included in either outcome analysis is also not reported.

The study is single-group and open-label, with no randomized comparator. This prevents a controlled estimate of the difference between cariprazine and another treatment or a control condition. The design also leaves changes over time open to explanations other than treatment. This is a design limitation, not a claim about the direction of any unreported result.

The primary outcome population is defined using baseline and post-baseline assessments, but the record does not state how missing Week 16 data were handled or whether sensitivity analyses were conducted. It does not report an analysis plan, model details, multiplicity methods, or a statistical justification for the enrollment target. These details are not reported in the registry record.

The arm description is truncated after stating that dose increases depended on inadequate response and absence of tolerability issues. Further details about dose decisions are not reported. The safety information is descriptive and lacks a control group; the record also does not provide further event definitions or analysis details. Consequently, the reported safety counts do not support a comparative safety conclusion.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Long-term Safety and Tolerability of Cariprazine for Bipolar I Disorder — NCT01059539.
• Registry record last updated 2019-06-13; status last verified 2019-05.
• Results first posted 2019-06-13.
• 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 describes a completed Phase 3, open-label, single-group study of cariprazine in participants with bipolar I disorder, with enrollment of 403. The intervention arm is described as cariprazine 3–12 mg/day for 16 weeks. The primary outcome is change from baseline in YMRS total score at Week 16; the listed secondary outcome is change from baseline in MADRS total score at Week 16.

The YMRS description states that higher scores indicate worse manic symptoms and negative change indicates improvement. The record indicates two outcome measures and zero analyses, and does not report numerical results for either outcome. Safety figures include 34 serious adverse events and 293 other adverse events among 402 at risk, with 0 deaths. Because the study has no randomized comparator, these safety figures are descriptive rather than comparative.