A Trial of the Fatty Acid Amide Hydrolase Inhibitor Palmitoylethanolamide in Bipolar Depression: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Trial of the Fatty Acid Amide Hydrolase Inhibitor Palmitoylethanolamide in Bipolar Depression (NCT06229977), a randomized phase 2 study. The primary outcome is Change in Depression as Assessed by the Hamilton Depression Rating Scale (HAM-D).

2. Clinical Question

3. Trial Design

This was a randomized, triple-masked, parallel-group Phase 2 trial. The registry lists the condition as bipolar depression and the interventions as PEA, placebo, and Treatment as Usual. The two results groups are PEA plus TAU and placebo plus TAU. The trial status is completed. The registry records a start date of 2023-05-17 and a primary completion date of 2025-07-17.

The registered enrollment is 34. That is the enrollment figure, not the number included in every endpoint analysis. For the primary outcome, the registry specifies an analysis population with both baseline and Week 6 HAM-D scores available. The posted primary results list 16.0 participants for PEA plus TAU and 12.0 for placebo plus TAU. Those endpoint counts should not be treated as the randomized group sizes unless the registry explicitly says they are; it does not report randomized group totals in the result description.

The primary measure was change in HAM-D score from baseline to six weeks. The registry also lists secondary measures involving HAM-D remission, HAM-D response, MADRS change, and time to HAM-D response. Results are posted for the remission and response counts; values for the other listed secondary measures are not reported in the registry record in the posted result details. The registered purpose also mentions associations with endogenous cannabinoids and cytokine levels, but the registry record does not report results for these associations.

Specific details of sequence generation, allocation concealment, masking procedures, TAU content, and the statistical analysis plan are not reported in the registry record. The design labels alone do not establish how these procedures were implemented.

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

Analysis population for the primary outcome, as defined in the registry: Analysis includes participants with both a baseline and a Visit 4 (Week 6) Hamilton Depression Rating Scale (HAM-D) score available. 2 participants from the PEA plus Treatment as Usual (TAU) arm and 4 participants from the Placebo plus Treatment as Usual (TAU) arm discontinued the study prior to Visit 4 or had a missing Visit 4 assessment and were excluded.

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.

6. Primary Endpoint

The registry lists the primary outcome as Change in Depression as Assessed by the Hamilton Depression Rating Scale (HAM-D), measured over Baseline, 6 weeks follow up.

The primary endpoint is change in depression severity measured with the Hamilton Depression Rating Scale. The registry describes HAM-D as ranging from 0 to 26, with higher scores indicating greater depression severity. The change is calculated as the score at six weeks minus the baseline score, so a negative change indicates a reduction in severity over that period.

A change score provides a way to describe how participants’ measured symptom severity shifted during follow-up. Reporting the mean change for each group summarizes the average change among participants included in that group’s analysis. It does not, by itself, estimate the difference between groups after accounting for baseline values or other factors. A direct comparative estimate and its uncertainty would be needed to characterize the evidence for a group contrast more fully; such a primary comparison is not reported in the registry record.

HAM-D is used as a structured symptom rating in the trial. Its numerical scale supports measuring change, but a mean change alone does not describe every participant’s experience or establish the clinical meaning of an individual score. The registry’s stated interpretation is directional: negative values indicate improvement in depression severity. The posted arm means are negative in both groups, and the reported ranges indicate uncertainty around those arm summaries. The registry does not state the confidence level or method used to calculate those ranges.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change summarize?

For a continuous outcome such as HAM-D score, the mean change is the average of each analyzed participant’s change from baseline to follow-up. In this trial, change is defined as the Week 6 score minus the baseline score. Because lower HAM-D scores indicate less depression severity in the registry’s description, negative change values point toward improvement. A group mean condenses the observed changes into one summary; it does not indicate that every participant changed by that amount or in the same direction.

The reported primary results are arm-specific means with ranges. A range around an estimate communicates uncertainty, but its interpretation depends on how it was calculated. The registry record does not report the confidence level, calculation method, or whether the range is a confidence interval. It is therefore safest to read the ranges as the uncertainty bounds reported with the arm summaries, without assigning them a particular statistical interpretation not documented in the record.

Why is a direct group comparison important?

The question of whether PEA plus TAU differs from placebo plus TAU is a between-group question. Two separate arm means describe each group but do not, alone, provide a formal estimate of the contrast. A comparative analysis would quantify the difference between groups and its uncertainty, potentially accounting for baseline HAM-D scores or other prespecified factors. The registry record does not report such a primary comparative estimate, its confidence interval, or its p-value. General statistical principle: a direct contrast is more informative for a comparative treatment question than deciding from the relative size of two separate summaries.

The analysis population also shapes what the mean describes. The registry says the primary analysis includes participants with both baseline and Visit 4 (Week 6) HAM-D scores. This is an available-measurement population. If participants without follow-up scores differ from those with scores, a complete-measurement analysis may not represent all enrolled participants. The registry record does not report an approach for imputing missing scores or evaluating the effect of missing data.

What do the secondary p-values tell readers?

The remission and response outcomes are counts of participants, so their comparisons concern binary outcomes: a participant either met the registered outcome definition or did not. The posted comparisons are labelled as risk differences and include unadjusted p-values. A risk difference expresses the difference between group proportions, while a p-value describes how compatible the observed data are with a specified no-difference model under the test assumptions. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of an effect.

For the secondary outcomes, the unadjusted p-values are 0.445 for remission and 0.306 for response. The uncertainty intervals for the comparisons include no difference and also values in either direction. This means the results do not pin down a precise comparative effect. General statistical principle: intervals are useful because they show a range of effects compatible with the data under the analysis, rather than reducing interpretation to whether a p-value crosses a threshold. The registry record does not state the confidence level or interval method for these comparisons.

Why do planning illustrations differ from observed results?

Sample-size illustrations are planning calculations, not additional trial outcomes. The registry’s planning assumptions state a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation; the assumed effect is a stated fraction of the observed effect. The listed figures are participants per arm for target power levels. They illustrate how the required group size changes under those assumptions and effect scenarios. They are not observed power, and they do not demonstrate that the completed trial was designed around those assumptions.

The record does not report the trial’s original sample-size justification, target enrollment rationale, or whether the planning assumptions were used when designing the study. Calculations based on an observed effect can be especially uncertain when the estimate comes from a small study. A planning illustration should therefore be understood as conditional: it depends on its assumptions and is not a retrospective measure of how likely the trial was to detect an effect.

What remains unknown about the analysis?

The registry record does not report the primary endpoint’s statistical model, whether adjustment for baseline score was used, the planned handling of missing measurements, or a prespecified primary treatment contrast. It also does not report a multiplicity adjustment for the secondary analyses, a statistical analysis plan, or a protocol-defined analysis population such as intention-to-treat. Those details are relevant because they affect how estimates and p-values should be interpreted. Without them, the posted summaries can be described, but they cannot be assumed to represent a particular unreported analysis method.

10. Multiplicity, Missing Data and Analysis Populations

The primary analysis population is defined by availability of both a baseline and a Visit 4 (Week 6) HAM-D score. This means the posted primary summaries do not necessarily include everyone enrolled. The registry record notes that 2 participants in the PEA plus TAU group and 4 participants in the placebo plus TAU group discontinued before a visit description that is truncated after the text 'Vis'. The intended visit wording is not reported in the registry record. The posted primary group counts are 16.0 and 12.0.

The record does not report how missing Week 6 scores were handled beyond defining the available-score population. It does not say whether missing values were imputed, whether sensitivity analyses were conducted, or whether reasons for missing measurements were compared across groups. General statistical principle: missing data can affect interpretation if the likelihood of missingness is related to participants’ outcomes or characteristics. An analysis restricted to people with measured outcomes may be biased if those retained differ systematically from those not measured.

The registry record does not report whether the primary analysis followed an intention-to-treat principle, a per-protocol principle, or another prespecified population definition. It does not report the statistical analysis plan, a primary between-group model, baseline adjustment, interim analyses, or a multiplicity strategy. The absence of these details does not show that no such procedures existed; it means they are not reported in the registry record.

Multiplicity matters because the registry lists several secondary outcomes, while numerical results are posted for only some of them. The reported remission and response p-values are unadjusted. Without a stated hierarchy or adjustment, the secondary comparisons should not be treated as a set of confirmatory tests. The lack of reported results for other listed endpoints also limits assessment of the full outcome pattern. These gaps call for cautious interpretation of the available summaries rather than assumptions about the analysis that was planned or performed.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for 18 participants at risk in the PEA plus TAU group and 16 at risk in the placebo plus TAU group. It records 0 serious adverse events in each group. It also records 0 deaths in each group. The record lists 3 other adverse events in each group, among 18 and 16 participants at risk, respectively. The registry does not list serious adverse event terms.

These figures are descriptive safety counts. A recorded zero serious adverse events means none were reported in the registry results for the listed groups; it does not establish that the risk of a serious event is absent. The number of participants at risk is the denominator reported for these safety summaries, and it differs from the primary endpoint analysis counts. These safety figures should not be combined with the efficacy analysis population.

The registry record does not report the nature, severity, timing, or relatedness of the other adverse events, nor does it provide a detailed account of how events were collected. It is therefore not possible to characterize those events further from the posted information. Comparisons of safety counts also require caution when the groups are small and event counts are limited. These descriptive data do not establish that either intervention caused or prevented an adverse event.

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

The posted primary results show negative mean HAM-D changes in both groups over the baseline-to-Week 6 interval among participants with the required scores. Under the registry’s definition, negative change indicates improvement in depression severity. The arm means and their reported ranges describe the observed outcome summaries, not a complete causal comparison of PEA plus TAU with placebo plus TAU.

The record does not report a primary between-group estimate or a formal test for that endpoint. The secondary remission and response results have unadjusted comparisons with uncertainty spanning no difference. Those findings do not establish equivalence, and they do not establish that one group is superior. A lack of a clear difference in the posted summaries is not proof that the interventions have identical effects. More generally, statistical uncertainty concerns the range of effects compatible with the data and analysis; it does not alone determine clinical importance.

The result also does not establish that PEA works or does not work for bipolar depression. The registry’s results describe a particular trial, its specified groups, and its available outcome measurements. The number enrolled, the endpoint analysis population, missing-data handling, and the unreported primary comparison all constrain what can be concluded. The record’s stated objective concerning endogenous cannabinoids and cytokines cannot be evaluated from these posted results because association results are not reported in the registry record.

General interpretation: a trial’s numerical findings are most useful when the outcome definition, comparative estimate, uncertainty, analysis population, and analysis plan can be considered together. Here, the posted data support a description of within-group HAM-D change and selected secondary counts, but the registry record does not report enough comparative analysis detail to make a firm inference about a between-group effect. The safety figures are likewise limited descriptive counts, not a comprehensive assessment of risk.

13. Why This Trial Matters Statistically

This trial illustrates why the distinction between within-group change and a between-group treatment comparison matters. Both groups have negative primary mean changes, but those summaries answer how the analyzed participants changed on average within each group. They do not, by themselves, answer whether adding PEA rather than placebo produced a different average change. A formal comparative estimate and its uncertainty are needed for that question, and the registry record does not report them for the primary endpoint.

It also illustrates how the analysis population affects interpretation. The primary results are based on participants with both baseline and Week 6 HAM-D scores, whereas safety counts use their own reported at-risk groups. Those populations should not be treated as interchangeable. The registry’s notes about discontinuations and the absence of a reported missing-data strategy make it important to distinguish outcome availability from enrollment.

The secondary results demonstrate another statistical point: a small set of event counts can yield uncertain comparative estimates, and unadjusted p-values do not account for examining multiple outcomes. Results across related endpoints can provide context, but they should not be treated as confirmation when the analysis hierarchy and multiplicity approach are not reported.

Finally, the sample-size illustrations are planning scenarios based on stated assumptions and fractions of an observed effect. They are not observed power and do not establish the original design rationale. Keeping planning calculations, observed summaries, and formal comparative analyses distinct is essential to interpreting a clinical trial record accurately.

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.

Several limitations are specific to the information available for this trial. The primary outcome is reported as separate arm means and ranges, but the registry record does not report a formal between-group estimate, its uncertainty, or a p-value. That omission limits direct interpretation of the primary comparative question. The reported endpoint population requires both baseline and Week 6 HAM-D scores, so the primary summaries reflect participants with those measurements rather than necessarily everyone enrolled.

The registry’s description of discontinuations is truncated after 'prior to Vis'. Although it reports 2 discontinuations in the PEA plus TAU group and 4 in the placebo plus TAU group, the intended visit wording is not reported in the registry record. The record also does not describe reasons for discontinuation, the handling of missing outcome scores, or sensitivity analyses. These omissions make it difficult to assess whether the observed-score population may differ from the enrolled population in outcome-relevant ways.

Numerical results are reported for two of the listed secondary endpoints, while results for the remaining listed measures are not reported in the registry record. The posted secondary tests are unadjusted, and no multiplicity plan is reported. The registry also does not report the statistical analysis plan, baseline-adjustment method, outcome assessor procedures beyond the triple-masking label, or details of Treatment as Usual. The design label does not resolve these operational details.

For safety, the record gives serious-event counts, deaths, and other adverse-event counts, but does not describe event types or relatedness. Its sample-size illustrations are conditional planning calculations and are not evidence about the study’s original design or achieved power. Together, these limitations mean the posted record supports a careful description of the recorded results, but not assumptions about unreported methods or unposted outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Trial of the Fatty Acid Amide Hydrolase Inhibitor Palmitoylethanolamide in Bipolar Depression — NCT06229977.
• Registry record last updated 2026-08-13; status last verified 2026-07.
• Results first posted 2026-08-13.
• 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 a completed randomized, triple-masked, parallel-group Phase 2 trial of PEA plus Treatment as Usual versus placebo plus Treatment as Usual for bipolar depression. The listed enrollment is 34, and the recorded dates are 2023-05-17 for study start and 2025-07-17 for primary completion.

The primary endpoint is mean change in HAM-D score from baseline to Week 6 among participants with both measurements. The posted arm means are -12.38 for PEA plus TAU and -13.03 for placebo plus TAU. A formal primary between-group analysis is not reported in the registry record. Secondary remission and response counts and unadjusted comparisons are posted; results for the other listed secondary measures are not reported in the registry record.

The registry reports 0 serious adverse events and 0 deaths in each safety group, alongside 3 other adverse events in each group. Missing-data methods, multiplicity handling, the statistical analysis plan, and results for the stated biological associations are not reported in the registry record.