Scopolamine in Bipolar Depression: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Scopolamine in Bipolar Depression (NCT04211961), a randomized phase 2 study. The primary outcome is Hamilton Depression Rating Scale Score After Last Treatment.

2. Clinical Question

The registry describes the trial’s objective as investigating the efficacy and safety of intravenous scopolamine compared with placebo in reducing depressive symptom severity. The posted primary outcome is the score after the final scheduled treatment, rather than a reported change from baseline. The record does not report a primary outcome contrast with a confidence interval, nor does it describe a baseline-adjusted estimate.

The primary summaries give the median score and inter-quartile range for each group. On this scale, higher values indicate greater depression severity. The sponsor reports a Wilcoxon (Mann-Whitney) comparison between the groups, with p = 0.3. This result should be read as a comparison of the posted score distributions at that outcome time, not as proof that the groups were equivalent or that any difference was caused by treatment. The record does not report a threshold defining a clinically important score difference.

The clinical question is therefore bounded: it concerns a particular symptom score at a specified post-treatment visit in the registered population. The results do not, by themselves, answer questions about other populations, longer-term outcomes, or treatment decisions.

3. Trial Design

NCT04211961 is listed as a completed, randomized, parallel-group, phase 2 trial. The brief summary describes it as a single-site, phase IIb study, and identifies the study as SCOPE-BD. Its official title describes a randomized, double-blinded, placebo-controlled trial in individuals with bipolar disorder experiencing a depressive episode. The registry lists quadruple masking. Which roles were masked is not reported in the registry record.

The registry lists enrollment of 55. The posted primary outcome summaries include 24 participants in each arm. These outcome denominators should be read as the populations represented in those summaries, not as a replacement for the registry’s enrollment figure. The record does not report why those denominators differ from the enrollment figure or how missing outcome observations were handled.

Participants assigned to scopolamine received one 15-minute intravenous infusion at 4 visits. Participants assigned to placebo received one 15-minute IV infusion of 100ml saline at 4 visits. The timing or dose of scopolamine is not reported in the registry record. The primary outcome was the Hamilton Depression Rating Scale score after the last treatment, at Visit 6, approximately 2 weeks after randomisation.

The registry records a start date of 2021-03-23 and a primary completion date of 2024-02-22. It lists the trial status as completed. The record does not report the randomisation sequence method, allocation concealment procedures, protocol deviations, or the precise analysis population used for the primary comparison. It also does not report the protocol’s planned sample-size justification or whether interim analyses were conducted. These omissions limit assessment of the trial’s implementation and analysis decisions from the registry record alone.

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: Of the 55 participants who consented, 5 were withdrawn pre-randomisation. Three participants were deemed to have HDRS scores below the acceptable eligibility range (\<14). A single participant was withdrawn by PI due to being medically (physically) unfit to continue. A single participant withdrew consent due to difficulties with cannulation. Fifty participants were randomised into the SCOPE-BD trial.

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.

Population: Consenting participants who were randomised.

6. Primary Endpoint

The registry lists the primary outcome as Hamilton Depression Rating Scale Score After Last Treatment, measured over Approximately 2 weeks after randomisation (Visit 6).

The primary endpoint is the Hamilton Depression Rating Scale score after the last scheduled treatment, at Visit 6, approximately 2 weeks after randomisation. The registry describes the score as a measure of objective depressive symptom severity. Its possible range is 0-54, with higher scores indicating greater severity.

A symptom score is useful as an endpoint because it represents severity on a common scale, allowing the outcome distribution in the randomized groups to be compared. In this record, the primary summaries use medians and inter-quartile ranges. Those summaries describe the centre and middle spread of the observed scores; they do not describe every participant’s experience or the shape of the full distribution. The record does not report a mean score or standard deviation for this outcome.

The endpoint is a score at a specified visit, not a change score. Baseline scores and a baseline-adjusted treatment estimate are not reported in the registry record. Consequently, the posted summaries answer a limited question about scores after the last treatment, rather than directly quantifying individual improvement from baseline.

The primary endpoint is distinct from the remission and response outcomes listed as secondary measures. A continuous symptom score and a binary classification capture different aspects of the outcome: one retains information across the scale, while the other depends on a classification rule. The registry record does not report the threshold used to define remission or response, so those definitions cannot be evaluated from the record alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary test compare?

The primary analysis is reported as a Wilcoxon (Mann-Whitney) test. In general, this rank-based method compares the relative ordering of observations across two groups. It can be useful when an analysis is framed around distributions rather than a comparison of means, and it does not require the same assumptions as a conventional two-sample mean comparison. A significant rank test does not automatically mean that the medians differ by a particular amount; its interpretation depends on the distributions being compared.

The registry reports medians and inter-quartile ranges for the primary outcome, which describe central tendency and spread in a way that fits the reported rank-based comparison. These summaries do not show the individual scores, the full distribution, or the extent of overlap between groups. The record does not report an estimated between-group difference or a confidence interval for the primary endpoint. As a result, the reported p-value cannot convey the size or precision of a primary treatment contrast.

How should a p-value be read?

In general, a p-value describes how compatible the observed data are with a specified statistical null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the probability that a result was caused by chance. It also does not quantify clinical importance. The primary reported p-value is 0.3. The registry record does not provide a primary confidence interval or a prespecified threshold for interpreting the score difference, so the p-value should be considered alongside the posted distributions and the limits of the record.

What do the binary-outcome estimates add?

For binary secondary outcomes, the posted recalculations express the contrast as a risk difference and give confidence intervals. In general, a risk difference expresses the difference between the proportions with an outcome in two groups, while its confidence interval indicates the range of estimates compatible with the data and the calculation method. Intervals that include no difference are compatible with a range of possible effects, including no difference; broad intervals indicate limited precision. The recalculated estimates are unadjusted and are not substitutes for the sponsor’s reported analyses.

Small counts can make estimates for binary outcomes imprecise. For example, remission counts are low in the posted groups. With few outcome events, moving only a small number of observations can have a substantial influence on the estimated contrast. Exact methods, such as Fisher’s exact test, can be used for sparse categorical data. Other methods, including a chi-squared test, use different approximations. Their p-values need not be numerically identical even when they use the same observed counts.

Why can the sponsor’s test and a recalculation differ?

Recalculated comparisons use simple unadjusted calculations from posted summary statistics. They may not reproduce all features of an original analysis, such as its analysis population, covariate adjustment, missing-data handling, or specific test implementation. The registry record does not report those details for every analysis. For binary outcomes, the record identifies Fisher Exact or Chi-squared methods for the sponsor’s reported analyses, while the recalculated comparisons are based on the available counts. Differences between these results should therefore be read as differences between analysis approaches, not as evidence that one set of numbers has been verified against participant-level data.

The sponsor’s own analysis takes precedence if a discrepancy is flagged. No discrepancy is flagged in this record. That does not establish that a recalculation is identical to the sponsor’s method; the reported tests and the unadjusted recalculations should still be distinguished.

What does the planning illustration mean?

The sample-size illustration is based on the observed effect, not on the trial’s documented design. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustration considers planning for 100%, 75%, and 50% of the observed effect, with target power levels of 80% and 90%. These are hypothetical planning scenarios, not observed power and not evidence that the trial was designed with those assumptions. The registry record does not report its own sample-size justification, so the illustration cannot establish what the investigators planned or whether the completed enrollment met a protocol target.

In general, planning for a smaller effect requires more participants to distinguish that effect from random variation at a chosen significance level and power. This relation depends on the assumptions used, including the effect size, allocation, outcome variability, and analysis method. An illustration derived from an observed result is especially uncertain as a basis for future planning because the observed effect itself may be imprecise. The displayed planning scenarios should be treated as examples rather than as a definitive recommendation.

What statistical details remain unavailable?

The registry record does not report the primary confidence interval, a detailed statistical analysis plan, the prespecified hierarchy among outcomes, or whether secondary tests were adjusted for multiple comparisons. It also does not report the precise analysis populations, how missing values were handled, or whether sensitivity analyses were performed. These details matter because they can affect uncertainty, the set of observations analyzed, and the interpretation of several outcome tests. General statistical principles can explain what the listed methods do, but they cannot fill in analysis decisions absent from the registry record.

10. Analyses Reported by the Sponsor

The sponsor’s primary analysis is a Wilcoxon (Mann-Whitney) comparison of the Hamilton Depression Rating Scale scores, reported with p = 0.3. The registry does not report a numerical contrast or confidence interval for that primary test. The posted arm summaries give the medians and inter-quartile ranges, but they do not permit a complete reconstruction of the original analysis or its underlying data.

For some binary secondary outcomes, unadjusted recalculations from posted counts accompany the sponsor’s reported tests. For remission at followup, the recalculated unadjusted p-value is 0.171, while the sponsor reports p = 0.3 using Fisher Exact. For response after the last IV treatment, the recalculated unadjusted p-value is 0.54, while the sponsor reports p = 0.5 using Chi-squared. For remission after the last treatment, the recalculated unadjusted p-value is 1.0, while the sponsor reports p > 0.9 using Fisher Exact.

The differences reflect that a recalculation from posted summaries is not necessarily the same computation as the sponsor’s test, and reported values may also be rounded. The record does not provide participant-level data to reproduce the sponsor’s methods. No discrepancy is flagged. The sponsor’s reported analyses remain the trial’s own analysis results; the unadjusted recalculations are supplementary and should not be treated as replacements.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures and 12 analyses, and 13 secondary outcomes are posted. Testing multiple outcomes raises a multiplicity issue: even if each test is conducted as planned, the chance of at least one apparently unusual result can increase as more hypotheses are examined. In general, a prespecified hierarchy or adjustment method can help control how a collection of tests is interpreted. The registry record does not report whether secondary outcomes were prioritized, whether multiplicity was addressed, or whether the listed analyses were prespecified.

Without those details, individual secondary p-values should not be treated as independent confirmatory evidence. The reported primary endpoint remains the principal result, while secondary analyses are more appropriately viewed as supportive or exploratory unless a protocol or analysis plan establishes otherwise. The record does not report such a hierarchy or plan.

Missing-data handling is also not reported in the registry record. The primary outcome summaries have n = 24 in each arm; the followup remission summaries have n = 24 in the placebo group and n = 23 in the scopolamine group. These different denominators show that the posted outcome populations vary across measures. They do not establish why observations are absent, whether participants withdrew, or how missing values were treated.

The record does not report whether the primary analysis followed an intention-to-treat principle, whether there were per-protocol or other analysis populations, or whether sensitivity analyses assessed the effect of missing data. These omissions matter because conclusions can depend on which participants are included and on assumptions about unobserved outcomes. The registry’s enrollment figure of 55 is not, by itself, enough to determine the analysis population for each outcome.

The record also does not report an interim-analysis plan, stopping rules, or a detailed protocol statistical analysis plan. It is therefore not possible to assess whether any unreported analysis decisions affected the interpretation. These limitations do not imply that inappropriate procedures were used; they identify information not reported in the registry record.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: depressed mood (4.2%), emotional distress (3.8%), suspected suicide (3.8%).

The registry reports serious adverse events affecting 1 participant in the placebo group, with 24 at risk, and 3 participants in the scopolamine group, with 26 at risk. It reports deaths of 0 in the placebo group and 1 in the scopolamine group. The record also lists other adverse events affecting 14 participants in the placebo group and 25 in the scopolamine group, with 24 and 26 at risk, respectively. These are counts within the safety groups reported in the registry.

The top serious adverse-event terms listed are Depressed mood at 4.2%, Emotional distress at 3.8%, and Suspected suicide at 3.8%. The record does not provide the denominator or event-level context for these term percentages in the registry record reported alongside them. The terms should not be interpreted as establishing a causal relationship to either intervention.

These counts are descriptive, not a precise comparison of safety risk. The safety group sizes are limited, and the registry record does not report further detail about event timing, severity grading, relatedness assessments, or participant-level overlap among event categories. The counts alone cannot establish whether an event was caused by treatment or estimate the range of possible differences in risk. They should be read as the adverse-event information posted in the registry, with those limits in mind.

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

The registry results provide a record of a randomized, placebo-controlled comparison of intravenous scopolamine and saline placebo for bipolar depression. The primary outcome is the Hamilton Depression Rating Scale score after the last scheduled treatment. The posted medians are 12.0 for placebo and 13.0 for scopolamine, and the sponsor’s Wilcoxon (Mann-Whitney) test reports p = 0.3. Higher scores indicate greater depression severity, but the medians and p-value do not establish the size or clinical importance of a treatment effect.

The result does not show that the treatments are equivalent. Demonstrating equivalence would require an appropriate design, a prespecified equivalence margin, and a suitably precise estimate; those are not reported in the registry record. Nor does the result prove absence of an effect. The primary comparison lacks a reported confidence interval, and the available summaries cannot establish which effects remain compatible with the data.

The secondary outcomes do not provide a basis for a definitive conclusion either. They include several outcome types and timepoints, and the registry record does not report how multiplicity was addressed. Some secondary counts are sparse, and some outcome values are missing or not estimable for a two-arm comparison. The analysis populations and missing-data methods are not reported.

The trial’s posted enrollment figure and the arm-specific outcome denominators do not resolve how many participants contributed to each analysis or why denominators differ. The safety counts describe reported events but cannot on their own establish causality or comparative safety with precision.

In general, a randomized design helps structure a comparison between groups, but the strength of the conclusions still depends on outcome completeness, analysis methods, precision, and transparent reporting. The record supports a cautious description of the observed summaries and reported tests. It does not, by itself, establish that scopolamine does or does not work, nor does it answer questions beyond the trial population, endpoint, and followup represented in the registry.

14. Why This Trial Matters Statistically

This trial illustrates why statistical interpretation should separate the estimated outcome pattern from the certainty of the comparison. The primary endpoint is a symptom score summarized by medians and inter-quartile ranges, with a rank-based test. Those elements describe the observed data in different ways: the summaries convey central location and spread, while the test addresses a distributional comparison. Neither gives a direct estimate of a clinically meaningful treatment difference in the absence of a reported contrast and confidence interval.

The record also illustrates how outcome populations can vary. The primary summaries have n = 24 in each arm, while a posted followup outcome uses n = 24 and n = 23. Reading each denominator in relation to its specific outcome is essential; the registry enrollment figure alone does not describe the data contributing to every analysis. Missing-data methods and analysis populations are not reported, so the impact of these differences cannot be evaluated.

Secondary outcomes add breadth but also create interpretive demands. Remission, response, and symptom scores do not measure precisely the same thing, and a collection of unadjusted tests can generate results that appear more informative than the evidence warrants. The record does not report a multiplicity plan or a hierarchy that would distinguish confirmatory from exploratory analyses.

Finally, a sample-size illustration derived from the observed effect is not a report of the trial’s design rationale and is not observed power. Separating those concepts helps avoid using post hoc planning calculations as proof that a study was adequately powered. The registry record does not report the trial’s own sample-size justification. Taken together, these features make this trial a useful example of how design, denominators, precision, and reporting completeness shape the strength of statistical conclusions.

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 registry record gives limited information about the enrolled population beyond bipolar disorder and a depressive episode of at least moderate severity. Further participant characteristics are not reported in the primary outcome description, limiting assessment of how broadly the results may apply. Although the summary describes a single-site trial, details about the site and recruitment are not reported in the registry record.

The primary outcome is reported as a score at Visit 6. Baseline scores, change from baseline, a treatment contrast, and a confidence interval for the primary comparison are not reported. This leaves the magnitude and precision of any between-group difference unclear. The registry describes a possible scale range of 0-54 and notes that higher values indicate greater severity, but it does not report a threshold for clinical importance.

The arm denominators vary across posted outcomes, and the registry does not report the reasons or missing-data procedures. The analysis population and whether all randomized participants were included in the primary analysis are not reported. That uncertainty restricts assessment of potential bias from exclusions or missing observations.

Other limitations concern analysis transparency. The randomisation method, allocation concealment, detailed analysis plan, multiplicity handling, and interim-analysis procedures are not reported in the registry record. Definitions of remission and response are also not reported. The secondary outcomes include diverse measures, and values are missing or not estimable for a two-arm comparison for another endpoint. Safety information is presented as counts, without the additional event-level details needed to evaluate timing, relatedness, or overlap.

These are limitations of what can be assessed from the registry record; they do not establish that the trial lacked procedures or that its results are invalid. They mean that the posted summaries support a narrower interpretation than a complete report with protocol, participant flow, and detailed analyses would allow.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Scopolamine in Bipolar Depression — NCT04211961.
• Registry record last updated 2025-04-29; status last verified 2025-04.
• Results first posted 2025-04-29.
• 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

NCT04211961 is a completed randomized, parallel-group, phase 2 trial described in its brief summary as a single-site, phase IIb, double-blind, placebo-controlled study. The registry lists enrollment of 55 and compares intravenous scopolamine with saline placebo in individuals with bipolar disorder experiencing a depressive episode of at least moderate severity.

The primary outcome is the Hamilton Depression Rating Scale score after the last treatment, approximately 2 weeks after randomisation. The posted median was 12.0 for placebo and 13.0 for scopolamine; the sponsor reports a Wilcoxon (Mann-Whitney) p-value of 0.3. A primary confidence interval and numerical treatment contrast are not reported in the registry record.

Secondary outcome results and safety counts are also posted, but interpretation is limited by multiple outcomes, varying outcome denominators, and unavailable details on missing data, analysis populations, and multiplicity. The posted results support a cautious description of this trial’s measured outcomes, not a definitive claim about treatment efficacy or safety.