Extension Study of Asenapine [P06107 (NCT01244815)] for Pediatric Bipolar Disorder (P05898): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Extension Study of Asenapine [P06107 (NCT01244815)] for Pediatric Bipolar Disorder (P05898) (NCT01349907), a non-randomized phase 3 study. The primary outcome is Number of Participants Who Experienced Clinical or Laboratory Adverse Events.

2. Clinical Question

3. Trial Design

This phase 3 study was an open-label extension of base trial P06107. Its stated purpose was to investigate the safety and tolerability of flexible-dose asenapine for long-term treatment of manic or mixed episodes associated with bipolar I disorder in children and adolescents who completed the base trial. The registry lists enrollment of 322 and a single-group, non-randomized design with no masking.

Although the registry reports two extension groups, those labels describe participants' treatment in P06107, not a randomized allocation within the extension. Participants previously treated with asenapine entered the Asenapine/Asenapine group; participants previously treated with placebo entered the Placebo/Asenapine group. Both groups received open-label asenapine in the extension, beginning at 2.5 mg twice per day, with planned increases to 5 mg twice per day at day 4 and 10 mg twice per day at day 7. Flexible dosing continued after day 7 for up to 50 weeks.

The registry lists the study as completed, with a start date of 2011-06-16 and a primary completion date of 2014-09-05. Rescue medication is also listed as an intervention. Details about its use, including criteria for starting it and how often it was used, are not reported in the registry record.

The extension design can describe events observed during asenapine treatment and follow-up, but it cannot isolate the effect of asenapine from the passage of time, prior treatment, or other differences between the groups. The groups are not like-for-like controls, and the registry record does not report a randomized comparison for the extension.

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: Participants who received at least one dose of trial medication, and were 17 years old or younger. One treated participant from the Placebo/Asenapine group, who was 18 years old, was excluded from this analysis.

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: Participants who received at least one dose of trial medication, and were 17 years old or younger. One 18 year old participant from the Placebo/Asenapine group, was excluded due to being overage.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Experienced Clinical or Laboratory Adverse Events, measured over Baseline (Day 1) to 30 days after the last dose of study drug (up to approximately 54 weeks).

The primary endpoint is the number of participants who experienced clinical or laboratory adverse events. The registry defines an adverse event as an unfavorable and unintended sign, symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to that product. The observation period ran from baseline on day 1 through 30 days after the last study-drug dose, for up to approximately 54 weeks.

A participant count is a binary-outcome summary: each participant is classified according to whether an event was recorded during the defined period. It provides a direct description of how many participants in each listed group experienced an event, but it does not show the number of separate event episodes or their duration. Nor does the count establish that the study drug caused an event; the endpoint definition expressly includes events whether or not they were considered related to the medicinal product.

Safety monitoring is relevant in a long-term extension because it records unfavorable clinical and laboratory events during continued treatment and follow-up. However, a broad count can combine events of different types and seriousness. The registry also reports serious-event counts separately. Interpretation therefore depends on the endpoint definition, the follow-up period, the population included in the analysis, and the non-randomized design.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level measure: a participant either experienced at least one event meeting the endpoint definition during follow-up or did not. For a binary outcome, counts are often accompanied by a proportion or a confidence interval. A confidence interval describes the uncertainty around an estimate under a specified statistical method; it is not a guarantee that the true value falls within its limits. The registry record reports participant counts and at-risk counts for the safety outcomes, but it does not report confidence intervals or inferential comparisons for them.

General statistical principle: describing each group separately is distinct from testing a between-group difference. A test or interval for a difference would require a defined comparison and assumptions appropriate to the study design. Here the extension is non-randomized, open-label, and both groups received asenapine. Thus, even a calculated difference in group outcomes would not by itself establish a causal effect of asenapine. Prior base-trial treatment defines the group labels, and the registry record does not report random assignment to extension groups.

The outcome definition also matters. “Any clinical or laboratory adverse event” is broad and includes events whether or not considered related to study medication. The record separately reports serious adverse events and other adverse events. A count of participants is not a count of event episodes: if a participant experienced more than one event, a participant-level endpoint would still count that person once for the relevant category. The registry record does not report individual-level data that would allow event histories or overlap between categories to be reconstructed.

The registry identifies additional outcomes: change from baseline in Young Mania Rating Scale (Y-MRS) total score; Y-MRS remission, defined as a total score ≤12; Y-MRS response; time to first total Y-MRS 50% response; time to failure to maintain Y-MRS response; and changes from baseline in Clinical Global Impression scales for overall bipolar illness, depression, and mania. These outcome definitions indicate different statistical questions. A change score compares measurements over time, a remission or response outcome classifies participants using a threshold, and a time-to-event outcome concerns when a defined event first occurs or when a response is no longer maintained. Results for these outcomes are not reported in the registry record.

General statistical principle: time-to-event methods can account for differing follow-up lengths and censoring, when their assumptions and event definitions are specified. The registry's outcome list includes time-to-event questions, but the statistical methods, censoring rules, and analysis results for those measures are not reported in the registry record. No particular time-to-event method should therefore be assumed for this study.

The registry lists no outcome analyses. The statistical analysis plan, including any models, covariate adjustments, confidence-interval methods, hypothesis tests, or interim analyses, is not reported in the registry record. It is therefore not possible to determine from the record whether the safety counts were adjusted for participant characteristics or whether formal comparisons were planned.

Sample-size illustrations, when presented, are planning exercises rather than observed trial results or evidence of observed power. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a fraction of the observed effect. For time-to-event outcomes, the stated convention is to give a total number of events, while other illustrations give participants per arm. These assumptions do not describe the actual extension design, which was non-randomized and single-group. Specific planning values and a sample-size justification are not reported in the registry record.

General statistical principle: over-dispersion matters when observed variability exceeds what a model assumes; ignoring it can make uncertainty estimates too narrow. That issue is most relevant to outcomes where the data are counts of repeated events, rather than this primary participant-level yes-or-no endpoint. The record does not report a repeated-event analysis or a model for event counts, so no such method can be attributed to the trial.

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("Asenapine/Asenapine", "Placebo/Asenapine")
n      <- c(241, 80)
events <- c(197, 74)
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  Asenapine/Asenapine  241  197  81.7  76.3  86.4  76.4  86.1  76.4  86.1
ARM  Placebo/Asenapine  80  74  92.5  84.4  97.2  84.6  96.5  84.6  96.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary outcomes spanning symptom-score changes, remission and response classifications, and time-to-event measures. When many outcomes are tested, the chance of obtaining at least one apparently notable result by chance can increase. General statistical principle: a prespecified multiplicity strategy can control or describe this issue, for example by adjusting tests or identifying a limited primary family of comparisons. The multiplicity strategy for this study is not reported in the registry record.

The registry record does not report outcome analyses for these secondary measures, nor does it report an analysis plan that would clarify which measures were confirmatory, how outcome time points were selected, or how repeated measurements were handled. The listed outcomes should therefore be read as planned or registered measures, not as evidence of findings.

Missing-data handling is not reported in the registry record. It is not stated how participants who discontinued, missed an assessment, or lacked a laboratory result were handled for each outcome. For a binary adverse-event outcome, the reported at-risk counts define the group summaries available, but they do not reveal the reasons for missing follow-up or whether participants had equal observation time. No imputation, censoring, or sensitivity-analysis approach should be presumed.

The primary endpoint population included participants who received at least one dose of trial medication and were 17 years old or younger. One treated participant in the Placebo/Asenapine group who was 18 years old was excluded from this analysis. Further analysis-population definitions, including the populations used for secondary outcomes, are not reported in the registry record.

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: suicidal ideation (2.9%), bipolar disorder (2.5%), depression (1.2%), swollen tongue (1.2%), drug hypersensitivity (1.2%).

The serious adverse event counts are 17 among 241 participants in the Asenapine/Asenapine group and 6 among 81 participants in the Placebo/Asenapine group. The group names refer to treatment in P06107; both groups received asenapine during the extension. These numbers describe participants with serious events, not the total number of separate serious-event episodes.

The listed serious-event terms and percentages are suicidal ideation (2.9%), bipolar disorder (2.5%), depression (1.2%), swollen tongue (1.2%), drug hypersensitivity (1.2%), and aggression (1.2%). The registry record does not explain whether a participant could contribute to multiple listed terms, nor does it provide details about timing, duration, or individual cases. The term-specific percentages should not be treated as comparative estimates between the extension groups.

Serious adverse events are distinct from the broader primary endpoint, which includes clinical or laboratory adverse events whether or not considered related to study medication. An observed event during treatment does not on its own establish causation. Deaths are not reported in the registry record. Because the study was open-label and non-randomized, these counts are descriptive safety information rather than evidence from a controlled treatment comparison.

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

The registry record describes adverse events observed during an open-label asenapine extension in children and adolescents who completed P06107. It provides participant counts for serious and other adverse events in two groups distinguished by their base-trial treatment. It also specifies that the primary safety analysis included treated participants 17 years old or younger and excluded one treated participant who was 18 years old.

These findings do not show what would have happened to comparable participants without asenapine during the extension: both groups received asenapine. Nor do they establish that recorded adverse events were caused by the study drug. The endpoint explicitly includes events whether or not considered related to the medicinal product. A non-randomized comparison between the groups cannot remove possible differences related to their prior treatment or other unreported characteristics.

The counts also do not describe the full clinical course of each participant. They do not convey how severe a non-serious event was, how long an event lasted, whether a participant experienced recurrent events, or the timing of events in relation to dose changes. Those details are not reported in the registry record. A participant count is useful for describing whether an event was recorded, but it cannot answer all questions about event burden or causation.

The registry lists additional symptom and time-to-event outcomes, but their results and analysis methods are not reported in the registry record. The available safety summaries should therefore be interpreted as descriptive information over the stated follow-up period, not as proof of benefit, harm, or comparative effectiveness. The record does not provide enough information to make a causal or comparative conclusion.

14. Why This Trial Matters Statistically

Extension studies address a different question from randomized efficacy trials. In this case, the registry describes continued, flexible-dose asenapine treatment for up to 50 weeks after completion of P06107. Longer observation can document events occurring during ongoing treatment and after the last dose within the defined follow-up period. It also brings interpretive challenges: the extension is open-label, non-randomized, and does not retain a placebo-treated extension group.

The two group labels can be easy to misread as a treatment comparison. They instead preserve the distinction between participants previously treated with asenapine and those previously treated with placebo in the base trial; both received asenapine in the extension. Recognizing that design feature is essential before interpreting the reported safety counts. The counts are useful descriptions of the recorded experience in the groups, but they are not a randomized estimate of treatment differences.

The endpoint also illustrates why statistical interpretation depends on what is counted. A participant-level adverse-event measure records whether participants experienced an event, while event terms and event episodes can provide other kinds of information. Serious-event counts and broad adverse-event counts answer related but distinct descriptive questions. Understanding these definitions helps prevent a participant count from being mistaken for an episode count or a causal conclusion.

Finally, the registry's outcome list is broader than the reported safety summaries. It includes symptom-score, remission, response, and time-to-event outcomes, but analyses for those measures are not reported in the registry record. Separating registered questions from reported results is important when assessing what the evidence can and cannot 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 central limitation for interpreting group differences is the extension's non-randomized, open-label design. Both groups received asenapine, and the labels reflect prior treatment in P06107. The groups therefore do not form a like-for-like randomized control comparison. Their safety counts cannot isolate an effect of extension treatment from prior-treatment history or other differences not described in the registry record.

The primary safety endpoint is broad and counts participants with clinical or laboratory adverse events, regardless of whether an event was considered related to the medicinal product. Group-level counts do not give event timing, duration, recurrence, severity for non-serious events, or participant-level overlap between event categories. The registry record does not report these details or deaths.

The endpoint population excludes one treated participant who was 18 years old and includes only those 17 years old or younger who received at least one dose. Additional population definitions for other outcomes are not reported in the registry record. The record also does not report how missing observations or unequal follow-up were handled.

Although multiple secondary outcomes are listed, their results, statistical methods, and multiplicity approach are not reported in the registry record. The analysis plan, including any adjustments, confidence intervals, hypothesis tests, interim analyses, or sample-size justification, is also not reported. These gaps limit assessment of precision and of how comprehensively the registered questions were evaluated.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Extension Study of Asenapine [P06107 (NCT01244815)] for Pediatric Bipolar Disorder (P05898) — NCT01349907.
• Registry record last updated 2024-05-22; status last verified 2022-02.
• Results first posted 2015-03-09.
• 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, non-randomized asenapine extension study for children and adolescents with bipolar I disorder who completed P06107. Flexible dosing continued for up to 50 weeks, following planned increases from 2.5 mg twice per day to 5 mg twice per day at day 4 and 10 mg twice per day at day 7.

The primary endpoint counted treated participants 17 years old or younger who experienced clinical or laboratory adverse events from baseline through 30 days after the last dose, for up to approximately 54 weeks. Serious and other adverse-event counts are reported for the Asenapine/Asenapine and Placebo/Asenapine groups. Both groups received asenapine during the extension, so the group counts are descriptive rather than a randomized comparison.

The registry lists additional symptom, remission, response, and time-to-event outcomes, but their analyses and the statistical analysis plan are not reported in the registry record.