Biomarker Changes and Anxiolytic Effects-Phase 2: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Biomarker Changes and Anxiolytic Effects-Phase 2 (NCT04565145), a randomized phase 2 study. The primary outcome is Mean PRKACA Change.

2. Clinical Question

The clinical question is whether the short-term kava regimen is associated with a different change in PRKACA than placebo among the adults studied. PRKACA is identified as the measured biomarker; the record says the broader study examines plasma and urinary biomarkers for anxiolytic properties of kava. That description does not establish that PRKACA is a validated measure of anxiety, nor does it state how a change in this biomarker should be interpreted clinically.

The record frames the study as an investigation of biomarker changes and anxiolytic effects, but the reported primary outcome is a biomarker measure. A difference in a biomarker is not, by itself, evidence of a difference in anxiety symptoms or other clinical outcomes. The registry record does not give a symptom endpoint, its result, or a planned relationship between symptom change and PRKACA change.

Although the study status is completed, the primary endpoint's data are not reported in a form that supports a single treatment-effect estimate in the registry record. The central question can therefore be described from the design, but the posted record does not establish the direction, size, or precision of a primary comparison.

3. Trial Design

This is a Phase 2 randomized, double-blind, parallel trial of a kava dietary supplement and placebo. The record gives enrollment as 39 and status as completed. It lists the University of Florida as sponsor. The study dates are 2021-04-05 for start and 2023-07-01 for primary completion.

The brief summary describes a one-week, double-blind, randomized, placebo-controlled trial in adults with generalized anxiety disorder. The kava regimen is described there as three 75 mg capsules per day. The arm description instead states 75 mg kava dietary supplement capsules per day for one week. Because the record does not reconcile these descriptions, the intended dose should not be inferred beyond those recorded wordings. The placebo arm is described as three placebo capsules per day for one week.

Randomization assigns participants to study arms according to a chance-based process, while double masking is intended to limit knowledge of assignment during the trial. The registry does not report how randomization was generated, who was masked, how masking was maintained, or whether masking was assessed. A parallel design means participants are assigned to an arm rather than described as crossing between treatments; the record does not report a crossover schedule.

The primary endpoint is a continuous measure: mean PRKACA change from baseline, before dosing, to one week after the first dose. The record identifies relative fluorescence units and standard deviation as the unit and dispersion measure. It does not report endpoint values, the number analyzed for this outcome, or a single primary treatment comparison. The record lists one outcome measure and zero analyses, but those listings do not give the missing endpoint result or explain the analysis approach.

The registry record does not report the allocation ratio, planned sample-size justification, detailed eligibility criteria, protocol deviations, or analysis population. Enrollment is not necessarily the number included in an endpoint analysis; the endpoint analysis population is not reported in the registry record.

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: Individuals were excluded it the met any of the exclusion criteria at screening or baseline.

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: Participants were enrolled and analyzed as described in the protocol

6. Primary Endpoint

The registry lists the primary outcome as Mean PRKACA Change, measured over From Baseline (pre dose) to 1 week after taking the first dose (post dose).

The primary endpoint is titled Mean PRKACA Change. It is described as the change in mean PRKACA value from pre-treatment to post-treatment, with measurement from baseline before dosing to one week after the first dose. The unit is relative fluorescence units, and the listed dispersion measure is standard deviation. This is a continuous biomarker endpoint: it records a quantitative measurement rather than a count of events or a time until an event.

Change from baseline is often used to describe how a measurement differs between an initial assessment and a later assessment. As a general statistical concept, using change can focus attention on within-participant movement over the study period. In a randomized trial, a comparison of changes between arms may help distinguish a pattern associated with assignment from changes that also occur over time in the comparator arm. The registry record does not report the numerical changes or a single between-arm comparison, so this interpretation cannot be applied to a particular estimate.

The record places the endpoint in a study of plasma and urinary biomarkers related to the anxiolytic properties of kava. It does not specify the specimen used for PRKACA in this endpoint, explain the biological interpretation of a higher or lower value, or report evidence linking the measure to anxiety symptoms. The endpoint's clinical meaning and the direction that would be considered favorable are therefore not reported in the registry record.

Without a reported estimate and its uncertainty, the endpoint label alone cannot show whether the arms differed, how large any difference was, or how precisely it was estimated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial is described as randomized, double blind, and parallel. These design terms describe how treatment assignment and observation were organized; they do not, by themselves, specify the statistical analysis. The registry record does not report the randomization method, the masking procedures, or the model used to analyze the primary endpoint.

What does randomization contribute?

As a general statistical concept, randomization is intended to make assignment independent of participant characteristics in expectation. It can reduce systematic differences between arms at the start of a study, although chance imbalances remain possible, especially in a small study. Randomization does not guarantee that every baseline characteristic will be balanced, and it does not remove concerns about missing measurements, adherence, or analysis choices. The record identifies randomized assignment but does not describe how the sequence was generated or concealed.

A parallel design assigns participants to a study arm for the trial rather than describing a sequence in which each participant receives both study conditions. Here, the registry identifies kava and placebo arms and a one-week regimen. It does not report the allocation ratio or whether all participants followed the assigned regimen. The record describes double masking, but does not identify which roles were masked or how the placebo was matched to the supplement.

What kind of endpoint is PRKACA change?

The primary measure is continuous and is reported in relative fluorescence units. The registered quantity is a mean change from baseline to one week after the first dose, with standard deviation as the dispersion measure. A mean describes the center of a set of values, while standard deviation describes how spread out individual values are around that mean. The registry does not provide the observed mean changes or standard deviations for either arm.

As a general statistical concept, an analysis can compare the change scores between randomized arms, compare follow-up values while accounting for baseline, or use another prespecified approach. These approaches can answer related but not identical questions and may have different assumptions. The analysis plan is not reported in the registry record, so it is not possible to determine which approach was used or whether an adjusted analysis was planned.

A confidence interval, in general, communicates uncertainty around an estimated effect under the model and sampling assumptions used. A narrower interval indicates greater precision under those assumptions; a wider interval indicates less precision. It does not account automatically for every source of uncertainty, such as measurement error, bias from missing data, or choices made after examining results. No confidence interval for a single primary comparison is reported in the registry record.

Why can dispersion matter?

Standard deviation describes variation among measurements, but it is not the same as the standard error of an estimated mean or treatment contrast. The standard error concerns the precision of an estimate and depends on the data and analysis. The record names standard deviation as the endpoint's dispersion measure but does not report standard errors or a model-based measure of uncertainty.

As a general explanation, over-dispersion occurs when observed variability is greater than a statistical model expects. For continuous outcomes, unusually high variability can make estimates less precise than a model assuming lower variability would suggest. The record does not report an over-dispersion assessment, and there is no basis to claim that over-dispersion occurred in this trial. More broadly, a model should reflect the outcome's distribution and the design; the relevant model details are not reported in the registry record.

What do the planning illustrations represent?

The registry's planning assumptions describe illustrative sample-size calculations based on an observed effect, not the trial's own design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial was designed around them. The sample-size justification for the trial is not reported in the registry record.

As a general statistical concept, a planning calculation asks how many participants per arm might be needed to detect a specified effect under chosen assumptions. Such a calculation depends on the effect size, outcome variability, significance threshold, allocation, and method. A planning illustration based on an observed effect is especially dependent on that estimate, which may itself be uncertain. It should not be interpreted as observed power or as proof that the trial had adequate precision. The registry does not provide a single primary effect estimate to interpret, and the planning illustrations do not replace that result.

Observed power is not a substitute for examining the estimate and its confidence interval. In general, post-study power calculations based on the observed effect largely reflect the result's uncertainty in another form. The registry's planning assumptions are explicitly described as illustrations, not the trial's design calculations. Their values should therefore be read as conditional planning information, not as a finding about the study's ability to detect an effect.

What does a p-value tell readers?

In general, a p-value measures how incompatible the observed data are with a specified null hypothesis under the statistical model. It does not quantify the size or importance of an effect, and it does not establish that the null or alternative hypothesis is true. Interpretation also depends on the analysis being appropriate and on whether the result was selected from multiple outcomes or analyses. No primary p-value or single comparison is reported in the registry record, so this framework cannot be used to interpret a PRKACA result from the record.

The record lists zero analyses and does not give an analysis plan. It is therefore not possible to determine whether the endpoint was analyzed with an unadjusted comparison, a baseline-adjusted model, or another method; whether model assumptions were checked; or how missing observations were handled. These are not details that can be inferred from the words randomized, double blind, or continuous.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome is not reduced to a single comparison in the registry record because it has several categories or time points. This limits interpretation: readers cannot identify one primary contrast and its estimate, uncertainty, or statistical test from the posted record. The endpoint description identifies baseline and the measurement one week after the first dose, but the record does not explain the categories or time points that led to the skip note.

As a general statistical concept, multiplicity arises when several outcomes, time points, groups, or analyses are examined. Testing many contrasts can increase the chance of obtaining an apparently notable result by chance if no adjustment or prespecified hierarchy is used. Methods such as defining a primary contrast in advance, adjusting for multiple testing, or treating analyses as exploratory can address different aspects of this issue. The registry record does not report a multiplicity plan, adjusted results, or whether any specific comparison was designated as primary within the endpoint categories.

Missing data are also important for a change endpoint, because assessing change generally requires measurements at relevant time points. The record does not report missing endpoint measurements, reasons for missingness, imputation methods, or sensitivity analyses. It does not state whether the endpoint analysis included all randomized participants, only participants with observed measurements, or another population. The analysis population is not reported in the registry record.

Enrollment is recorded as 39, but it should not be treated as the endpoint analysis count. The safety entries separately identify 10 at risk in each arm; those figures do not establish the number analyzed for PRKACA. Without an endpoint denominator and missing-data account, the completeness of the primary outcome data cannot be assessed.

The registry record does not report a statistical analysis plan, interim analyses, or a method for handling multiple comparisons. These omissions do not establish that such methods were absent in the conduct of the study; they mean the details are not reported in the registry record.

11. 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 non-serious adverse event terms

The serious adverse event entries report zero affected in the kava arm and zero affected in the placebo arm. Each arm lists 10 participants at risk for the serious-event entry. The record also reports zero deaths in each arm. These are the figures recorded; they do not describe the types of events assessed or how long participants were monitored for safety.

For other adverse events, the registry reports 4 affected in the kava arm and 3 in the placebo arm, with 10 at risk in each. The record does not give the event terms, severity, timing, recurrence, or whether events were considered related to study treatment. It also does not report a statistical comparison of these counts. They should be read as descriptive entries, not as an estimate of a causal treatment effect.

As a general statistical concept, adverse-event counts depend on how events are defined, collected, and monitored, as well as on how many participants were observed and for how long. A zero count of serious events in the registry entry does not establish that no event could occur or that the arms have equivalent safety. The short study description identifies a one-week regimen, but the safety monitoring duration is not reported in the registry record.

The safety entries do not replace the primary endpoint result, and they do not provide a complete safety profile. The registry record does not report additional detail needed to assess event patterns or compare safety formally.

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

The record supports a limited description of the trial: a completed Phase 2 randomized, double-blind, parallel comparison of kava and placebo, with a one-week regimen described in adults with generalized anxiety disorder. It identifies change in mean PRKACA as the primary endpoint. It also records serious and other adverse-event counts for the two arms.

The record does not establish whether the primary endpoint differed between arms. It does not provide a single primary comparison, a numerical effect estimate, a confidence interval, or a p-value. The outcome note explicitly states that the primary outcome has several categories or time points and was not reduced to one comparison. Without a defined contrast and its result, the magnitude, direction, and precision of any difference cannot be interpreted from the registry record.

The biomarker framing also sets a boundary on interpretation. The study summary describes an investigation of plasma and urinary biomarkers for anxiolytic properties, but the endpoint is PRKACA change. The record does not report a symptom result or a validated interpretation connecting PRKACA change to clinical anxiety outcomes. A biomarker finding, if reported, would not alone show that participants experienced a clinically meaningful change in anxiety.

The safety entries show zero serious adverse events and zero deaths in each arm in the registry record, alongside other adverse-event counts of 4 for kava and 3 for placebo. Those counts do not establish comparative safety: event detail, attribution, monitoring duration, and statistical analysis are not reported. They also should not be treated as proof that serious events are impossible.

The record's completion status does not fill these reporting gaps. The analysis population, handling of missing measurements, multiplicity strategy, and sponsor analysis are not reported in the registry record. The most defensible conclusion is therefore about what was registered and which outcome was named, rather than about a treatment effect.

13. Why This Trial Matters Statistically

This trial is statistically notable for the gap between a clearly named continuous primary biomarker endpoint and the absence of a single reported primary comparison. Knowing that mean PRKACA change was measured from baseline to one week after the first dose identifies the intended subject of analysis, but does not provide the estimate readers need to evaluate direction, magnitude, or precision.

The record also illustrates why a registry outcome label and a result are different forms of information. A title and measurement timeframe describe what investigators intended to assess. Interpreting an effect requires a defined contrast, a result, and an account of uncertainty. Here, the outcome note says multiple categories or time points prevented reduction to one comparison. The relevant categories and analysis choices are not reported in the registry record.

The design terms—randomized, double blind, and parallel—are valuable context, but cannot answer questions about the analytic population, missing endpoint data, or multiplicity. Those details affect how an estimate should be interpreted and are not reported in the registry record. Likewise, enrollment is not interchangeable with the number contributing measurements to an analysis.

The trial's biomarker focus makes the distinction between a laboratory measure and a clinical outcome especially important. The record describes an investigation of biomarkers related to anxiolytic properties, but does not report a symptom outcome or the clinical meaning of a PRKACA change. Statistical evidence about the biomarker, even if available, would need a separate clinical interpretation.

Finally, the safety entries demonstrate the limits of sparse event counts. They record no serious events and provide counts for other events, but without event terms, monitoring context, or an analysis, those entries cannot support a broad comparison. Careful reading separates registered design information, descriptive counts, and the primary effect that remains unreported.

14. 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 primary limitation for interpreting this trial from the registry record is that no single primary PRKACA comparison is reported. The record says the outcome has several categories or time points and was not reduced to one comparison. The numerical endpoint results, including any effect estimate and measure of uncertainty, are not reported in the registry record.

Details needed to understand the endpoint itself are also limited. The record does not specify the specimen used for PRKACA, the interpretation of higher or lower values, or how the biomarker relates to anxiety symptoms. While the brief summary describes an investigation of plasma and urinary biomarkers, it does not identify which specimen or specimens generated this particular endpoint. Nor does the record report a clinical symptom result.

The dose descriptions are not fully aligned: the brief summary says three 75 mg capsules per day, while the kava arm description says 75 mg capsules per day. The record does not clarify the intended amount. The placebo description states three capsules per day. This inconsistency should be preserved rather than resolved by assumption.

The endpoint analysis population, number with measurements at each time point, missing-data reasons, and missing-data methods are not reported. The statistical model, randomization implementation, allocation ratio, analysis plan, and any multiplicity strategy are also not reported in the registry record. The entry listing zero analyses does not clarify whether analyses were conducted elsewhere.

Finally, the safety information is sparse. Serious-event and death counts are recorded, as are counts for other adverse events, but the terms, treatment attribution, duration of monitoring, and formal comparisons are not reported. These limitations constrain interpretation of the registry information; they do not establish what may have been reported or analyzed outside the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Biomarker Changes and Anxiolytic Effects-Phase 2 — NCT04565145.
• Registry record last updated 2024-08-13; status last verified 2024-07.
• Results first posted 2024-08-13.
• 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.

18. Record Summary

The registry record describes NCT04565145, titled “Biomarker Changes and Anxiolytic Effects-Phase 2,” as a completed Phase 2 randomized, double-blind, parallel trial sponsored by the University of Florida. Enrollment is recorded as 39. The brief summary describes a one-week kava-versus-placebo study in adults with generalized anxiety disorder.

The primary endpoint is mean PRKACA change from baseline before dosing to one week after the first dose, measured in relative fluorescence units, with standard deviation as the listed dispersion. The record does not report a single primary comparison or its numerical result. It records zero serious adverse events and zero deaths in each arm, and other adverse events in 4 participants in the kava arm and 3 in the placebo arm, with 10 at risk in each arm.

The endpoint analysis population, missing-data methods, multiplicity approach, and detailed statistical analysis are not reported in the registry record.