Cognitive Effects of Oral p38 Alpha Kinase Inhibitor Neflamapimod in Dementia With Lewy Bodies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cognitive Effects of Oral p38 Alpha Kinase Inhibitor Neflamapimod in Dementia With Lewy Bodies (NCT04001517), a randomized phase 2 study. The primary outcome is Composite Z-score of a Study-specific Neuropsychological Test Battery (NTB) Including Tests From Cogstate Battery, Letter Fluency Test and Category Fluency Test.

2. Clinical Question

This clinical question concerns a measured cognitive test score, not every aspect of DLB or daily functioning. The protocol summary also lists secondary measures, including the Clinical Dementia Rating Scale-Sum of Boxes, Mini-Mental State Examination, Neuropsychiatric Inventory, Timed Up and Go Test, and electroencephalogram measures. Those outcomes address different domains and should not be treated as interchangeable with the primary composite. Their presence in the registry does not establish what their results were. The record identifies the study as randomized, double-blind, placebo-controlled, and parallel, with quadruple masking. It is marked completed, but completion status alone does not establish the direction, size, or precision of the cognitive contrast.

3. Trial Design

This was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel study of oral neflamapimod versus matching placebo in people with DLB. The registry reports 1:1 randomization and enrollment of 91 participants. It lists EIP Pharma Inc as sponsor and gives the study status as completed. The recorded study start was 2019-09-30, and the primary completion date was 2020-06-30.

The treatment period was 16 weeks. Neflamapimod and matching placebo were administered with food in 40 mg capsules, using either a BID or TID regimen according to the weight rule in the registry. In the primary analysis description, participants receiving placebo on either schedule were treated as one placebo group. The registry gives the rationale that placebo dosing frequency was not expected to produce different outcomes, and says this grouping followed the protocol and statistical analysis plan.

Masking is recorded as quadruple. The registry does not identify which roles were masked, so the exact meaning of that label for participants, clinicians, assessors, or analysts is not reported in the registry record. The record also does not describe the randomization sequence, concealment procedures, site count, eligibility criteria in detail, or participant flow by treatment group.

The primary endpoint was a composite z-score from a study-specific NTB. Assessments at baseline and on treatment were used in a mixed model for repeated measures, and the reported contrast was intended to represent the mean difference over the entire study course. The listed secondary outcomes span cognitive, neuropsychiatric, motor, functional, and EEG measures. The record does not report a detailed hierarchy among the secondary outcomes or how their results were handled statistically. Although the primary completion date and completed status are available, neither supplies the missing outcome estimates or an account of how many participants contributed data at each assessment.

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: All subjects with a baseline and at least one on-treatment NTB evaluation. As placebo given twice or three times a day would not be expected to differences in outcome, per the protocol and statistical analysis plan (SAP) the placebo group was considered as one group, regardless of whether they received placebo BID or TID.

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 Composite Z-score of a Study-specific Neuropsychological Test Battery (NTB) Including Tests From Cogstate Battery, Letter Fluency Test and Category Fluency Test, measured over As the analysis was by Mixed Model for Repeated Measures, all time points at which NTB was assessed utilized in the analysis. The difference reported is the mean difference over the entire course of the study..

The primary endpoint was change from baseline in a composite z-score from a study-specific Neuropsychological Test Battery. It included Cogstate Detection, Identification, One Card Learning, and One Back tests, along with Letter Fluency and Category Fluency. Each individual test score was converted to a z-score, and the six tests were weighted equally in the composite.

A z-score expresses a score relative to a reference mean and scale. In this endpoint, zero corresponds to the mean; negative values are below the mean and positive values are above it. The registry says there is no minimum or maximum value. It also defines positive change as improvement in cognition and negative change as worsening. These conventions describe the score; they do not establish that a particular observed change occurred in this trial.

A composite can combine information from several tests into one outcome, which may represent performance across more than one cognitive task. Equal weighting means each listed test contributes equally to the composite calculation, as described in the registry. The endpoint is used to assess cognition, the primary objective named in the study summary. Its interpretation remains specific to the tests and scoring method used; it is not a direct measure of every clinical feature or daily activity.

The registry specifies assessments at baseline, Week 4, Week 8, and Week 16, and says the mixed model used all time points at which the NTB was assessed. The posted primary result itself is not reported in the registry record, so neither the magnitude nor direction of the mean contrast can be interpreted.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a repeated-measures model do?

General statistical explanation: A repeated-measures model analyzes outcomes collected from the same participants on more than one occasion. It can use the pattern of measurements across time rather than reducing the analysis to a single follow-up assessment. Measurements from the same participant are related, so the model needs to account for that within-person relationship. The particular form of that relationship, the model’s covariance structure, and other implementation details are not reported in the registry record.

For this trial, the registry identifies a mixed model for repeated measures and says all time points at which the NTB was assessed were used. It defines the reported contrast as the mean difference over the entire course of the study. The described assessment schedule includes baseline and Week 4, Week 8, and Week 16. The record does not give the fitted model’s coefficients, group-specific estimates, standard errors for the contrast, or a confidence interval. A model label alone is not enough to reconstruct those results.

What does the mean difference represent?

General statistical explanation: A mean difference compares the average outcome between groups on a stated scale. For a change outcome, interpretation depends on how change is defined and on the direction of the scale. Here, the registry defines a positive change in the composite z-score as improvement and a negative change as worsening. It describes the primary comparison as an average contrast over the study, rather than reporting a separate primary estimate for each follow-up time.

A difference estimate would describe the size and direction of the contrast on the composite z-score scale. A confidence interval, if reported, would describe the range of values compatible with the estimate under the model and its assumptions. A p-value, if reported, would address compatibility with a specified null hypothesis under the statistical test. Neither the primary contrast estimate nor its uncertainty or test result is reported in the registry record, so none of these interpretations can be made for this trial’s primary outcome.

Why is the endpoint a composite?

General statistical explanation: Combining several measures can summarize performance across multiple tasks in a single outcome. It can also make interpretation less direct than a score from one familiar test, because the composite depends on its component measures and scoring rules. In this study, the registry says that each of six test scores was converted to a z-score and each test was weighted equally. It does not provide the individual test results or explain the reference data used to create each z-score. The composite’s stated direction is clear, but its actual change is not available in the registry record.

How should standard error and confidence intervals be read?

General statistical explanation: A standard error describes the sampling uncertainty of an estimate. It is not the same as the spread of individual participant scores. A confidence interval conveys uncertainty around an estimate in a range on the outcome scale. A narrower interval indicates greater precision than a wider interval, while an interval that includes values on either side of no difference may leave the direction of the contrast uncertain. These ideas explain how uncertainty measures are generally interpreted; the primary outcome’s standard error or confidence interval is not reported in the registry record.

The endpoint metadata identify the dispersion as a standard error, but do not provide a numerical primary estimate or the associated uncertainty in the registry record. No inference about statistical significance or precision can be drawn from the endpoint definition alone.

What do the planning assumptions mean?

General statistical explanation: A sample-size planning calculation asks how many participants an imagined study might require under stated assumptions about the target effect, allocation, significance level, and analysis. It is conditional on those assumptions; it does not describe the observed result or prove that a study had a particular probability of detecting an effect after completion.

The registry describes its planning illustrations as based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is expressed as a stated fraction of the observed effect. The illustrations are explicitly not the trial’s own design. Their numerical values and the observed effect used to generate them are not reported in the registry record. They must therefore be read as planning scenarios, not as observed power, a sample-size justification for the original trial, or evidence of treatment benefit.

Why can extra variability matter?

General statistical explanation: Over-dispersion means observed variability is greater than a model or distribution assumes. When that occurs, standard errors may be too small if the extra variability is not accounted for, making uncertainty appear less than it is. A model suited to the outcome’s variability can improve inference. The primary NTB outcome is described as continuous and analyzed with a mixed model for repeated measures. The registry does not report an assessment of over-dispersion or a specific adjustment for it, and the posted outcome details are insufficient to evaluate model fit.

More generally, readers need the estimate, an uncertainty measure, and enough model information to judge how the analysis relates to the data. The registry provides the broad method and outcome definition, but not the detailed statistical implementation or the primary result. The appropriate interpretation is therefore limited to what the design planned to estimate, not a claim about what the analysis found.

10. Multiplicity, Missing Data and Analysis Populations

The study lists a primary cognitive composite and several secondary outcomes, including measures of cognition, neuropsychiatric symptoms, motor performance, and EEG. Testing multiple outcomes can raise a multiplicity issue: when many hypotheses are examined, the chance of at least one apparently unusual result can increase. General statistical explanation: Researchers may address this by specifying a hierarchy, adjusting significance thresholds, or interpreting secondary analyses as exploratory. The multiplicity strategy, any outcome hierarchy, and any adjustment are not reported in the registry record.

The primary population is described as all subjects with a baseline and at least one on-treatment NTB evaluation. The registry also says the placebo group was treated as one group regardless of BID or TID schedule, following the protocol and statistical analysis plan. The number of participants in this analysis population, treatment-group counts, and the handling of participants with incomplete outcome data are not reported in the registry record.

General statistical explanation: Repeated-measures models can use available outcome observations under assumptions about the missing-data process. The validity of that approach depends on assumptions and implementation, and it does not make missing data irrelevant. The registry does not report the amount or reasons for missingness, the assumptions used for missing data, sensitivity analyses, or whether any imputation was performed. It also does not provide participant flow or the number analyzed at each visit.

The registry refers to a protocol and statistical analysis plan when explaining the combined placebo group, but does not report the full statistical plan in the record details. Details such as covariate adjustment, model structure, planned contrasts, handling of protocol deviations, and the multiplicity strategy 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: new brain lesions of unclear etiology (3.8%), diagnosis of brain tumor (3.8%), head injury (3.8%), hematochezia (2.2%), asthma exacerbation (2.2%).

The serious adverse event figures are reported separately for neflamapimod TID, neflamapimod BID, and placebo. The registry lists 20 participants at risk in the TID group and 0 affected by serious adverse events; 26 at risk in the BID group and 3 affected; and 45 at risk in the placebo group and 4 affected. It reports 0 deaths in each neflamapimod group and 2 in the placebo group. These are descriptive counts in the registry record. They do not by themselves establish whether an event was caused by treatment or whether groups differed in risk.

For other adverse events, the record lists 8 affected among 20 at risk in the TID group, 8 among 26 in the BID group, and 17 among 45 in the placebo group. These figures are separate from the serious adverse event counts and should not be combined with them. The record lists serious-event terms including new brain lesions of unclear etiology, diagnosis of brain tumor, and head injury, each reported as 3.8%; hematochezia, asthma exacerbation, and intraparenchymal hemorrhage are each reported as 2.2%. The registry does not give enough detail to interpret those percentages as comparative risks or attribute events to a treatment.

Adverse-event counts are not efficacy outcomes, and a count alone does not show severity, timing, recurrence, or causal relationship. The registry record’s safety figures should be read as reported event summaries, not as a causal comparison.

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

The registry establishes that a randomized, double-blind, placebo-controlled Phase 2 study was conducted to evaluate a cognitive endpoint in DLB. It describes the intervention, comparator, assessment schedule, composite score, and repeated-measures approach. These details clarify what the investigators intended to compare and how the primary outcome was defined.

They do not establish the result. The primary mean difference, group changes, uncertainty interval, and statistical test are not reported in the registry record. The endpoint’s scoring direction explains what positive or negative change would mean, but no trial-specific direction or magnitude can be inferred without the estimates. The same limitation applies to the listed secondary outcomes: their inclusion in the registry does not reveal their findings.

The registry’s sample-size material is described as a planning illustration based on the observed effect and stated assumptions. A planning calculation is not an outcome, and it is not observed power. Without the numerical illustration or primary estimate, it cannot clarify the size or precision of the treatment contrast. The completed status and enrollment of 91 also do not substitute for results or identify how many participants contributed to the analysis.

The safety summaries report serious adverse event counts and deaths by group, along with selected event terms and percentages. Descriptive differences in these counts cannot establish causation. The available information does not include enough context to assess event timing, relatedness, exposure, or comparative risk in detail.

Overall, the registry record supports a careful account of study design and planned statistical interpretation, but not a conclusion about the cognitive effect observed. It also does not provide the detailed analysis population, missing-data assessment, or statistical plan needed to evaluate all aspects of the reported analysis. These limits should remain explicit when describing what the record can establish.

13. Why This Trial Matters Statistically

This trial is statistically notable for its repeated-measures primary endpoint. Rather than defining the primary comparison only as a contrast at the final assessment, the registry says the analysis used all assessed NTB time points and reported a mean difference over the study course. That framing makes the treatment contrast a summary across repeated observations, so it differs conceptually from a single follow-up score.

The outcome also combines six cognitive tests after conversion to z-scores, with equal weighting. This creates a composite intended to represent performance across several tasks. Composite construction can be useful for summarizing related outcomes, but interpretation depends on knowing the component tests, their transformations, and the direction of the scale. The registry identifies these features and says positive change reflects improvement, while not providing the result itself.

The study’s placebo group combines participants on BID and TID schedules for the primary analysis. The registry says this approach followed the protocol and statistical analysis plan because different placebo dosing frequency was not expected to affect outcomes. Stating the grouping rule helps clarify the intended comparison, even though detailed analysis specifications are not available.

The record also illustrates why outcome reporting matters. A well-described endpoint and a named statistical model cannot show the size or precision of an effect without the estimate and its uncertainty. Likewise, enrollment and study completion do not reveal the analysis population or the consequences of missing assessments. For clinical researchers and biostatisticians, the record is a useful example of the distinction between a study’s design, the analysis it planned, and the results needed to interpret its findings. In this case, the registry entries support the first two descriptions more than any conclusion about the observed primary outcome.

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 main limitation for interpreting this specific trial is that the primary outcome result is not reported in the registry record. There is no primary contrast estimate, group-level change, confidence interval, standard error, or p-value in the registry record. The record therefore does not support an assessment of effect direction, magnitude, or precision.

The analysis population is described, but its size is not reported. Enrollment of 91 does not establish how many participants had a baseline and at least one on-treatment NTB evaluation. The treatment-group sizes used for the primary analysis, visit-level participant counts, participant flow, and reasons for missing assessments are not reported in the registry record. This prevents assessment of the amount and pattern of endpoint data contributing to the model.

The registry names a mixed model for repeated measures but does not report the model specification, covariance structure, covariates, or model diagnostics. The detailed handling of missing data, sensitivity analyses, and robustness checks is also not reported. The record identifies several secondary outcomes, but the multiplicity approach and any outcome hierarchy are not reported.

The composite endpoint is described in terms of its six components and equal weighting, but individual component results and details of the reference data for z-score conversion are not reported in the registry record. The primary contrast is described as a mean over the study course, while separate time-point estimates are not available.

Safety information is reported as event counts and selected terms, without enough context to assess timing, relatedness, or comparative risk. These limitations concern what can be interpreted from the registry record; they do not establish that additional information was or was not collected elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Cognitive Effects of Oral p38 Alpha Kinase Inhibitor Neflamapimod in Dementia With Lewy Bodies — NCT04001517.
• Registry record last updated 2023-06-29; status last verified 2023-06.
• Results first posted 2021-11-02.
• 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 describes a completed Phase 2, randomized, double-blind, placebo-controlled, parallel study of oral neflamapimod versus matching placebo in DLB. It reports 1:1 randomization, enrollment of 91, and a 16-week treatment period. The primary endpoint was change in a six-test composite NTB z-score, analyzed with a mixed model for repeated measures using assessments across the study.

The registry defines the score’s direction and describes the intended primary analysis population and combined placebo group. It also lists secondary outcomes and adverse-event summaries. The primary outcome estimate and its uncertainty are not reported in the registry record, nor are the primary analysis population size, missing-data details, or full statistical specifications. The record therefore describes the study question and method but does not permit interpretation of the observed primary cognitive contrast.