Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD (NCT03638466), a randomized phase 2 study. The primary outcome is Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task.

2. Clinical Question

3. Trial Design

This was a phase 2, randomized, quadruple-masked, parallel-group study. Enrollment was 7. The registry record identifies a high-dose SPN-810 arm and a placebo arm; both were added to a stable dose of optimized ADHD medication. The SPN-810 arm is labeled 36 mg, and its description specifies 18 mg twice a day. The placebo description also specifies twice-a-day dosing. The study began on 2019-05-30, had a primary completion date of 2019-11-07, and is listed as terminated.

The study was exploratory and focused on brain activity measured with functional magnetic resonance imaging during the point subtraction aggression paradigm. The paradigm was described as a behavioral aggression task involving provocation by a fictitious opponent who indirectly takes money from the participant. Magnetic resonance spectroscopy was also included as an assessment, with a secondary outcome concerning GABA and glutamate levels. The intervention list additionally names the PSAP task, fMRI, MRS, SPN-810, and placebo.

Randomization and masking are recorded, but details such as the randomization method, allocation concealment, masking procedures, and who was masked are not reported in the registry record. The reason for termination, the planned enrollment target, and whether recruitment stopped early are also not reported. The record does not state whether the termination was related to feasibility, safety, administrative decisions, or another reason, so no explanation should be inferred.

The study’s small enrollment means the posted group counts are limited: 4 participants were at risk in the placebo group and 3 in the high-dose SPN-810 group for the adverse-event summaries. The imaging analysis population is defined by availability of baseline and post-treatment scans, but the number satisfying that definition is not reported. The record lists seven outcome measures and no statistical analyses.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Completed population included all subjects randomized, who had a Baseline imaging scan (including the anatomical scan) and post-treatment imaging scans.

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: Randomized Population: The Randomized Population consists of all enrolled subjects who completed the Baseline Period including imaging scans, meet the inclusion/exclusion criteria and were randomized to SPN-810 36 mg or Placebo.

6. Primary Endpoint

The registry lists the primary outcome as Aggression-related Change in the Whole Brain in BOLD (Blood Oxygenation Level-dependent) Signal fMRI Contrast in Response to the PSAP Task, measured over Baseline/Visit 2 (Day -5) to Visit 5 (Day 28) for a total of 4 weeks..

The primary endpoint was the aggression-related change in whole-brain BOLD fMRI contrast during the PSAP task, expressed in voxels. BOLD imaging uses changes in blood oxygenation as an indirect measure of brain activity. The recorded contrast compares the neural response during an aggressive response with the response during a monetary response. Aggression was operationalized in the endpoint description using the number of Option 2 presses relative to total button presses and provocations.

The endpoint was defined as the post-treatment minus baseline change, measured from baseline/Visit 2 (Day -5) to Visit 5 (Day 28), for a total of 4 weeks. A positive value represents an increase in activity. The location of a peak value was to be described using Montreal Neurological Institute coordinates. The record specifies a mean and 95% confidence interval as the measure and dispersion, but does not report a numerical estimate or interval.

Using an imaging contrast allows investigators to examine task-related brain activity rather than relying only on a behavioral measure. In this exploratory study, the endpoint was intended to characterize changes in brain response associated with the aggression task. An imaging contrast is not itself a direct measure of clinical benefit, and interpretation depends on the task, the analyzed brain signal, and the analysis choices. The registry record does not provide enough results to assess the size, precision, or location of any observed change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry record is limited. It identifies a continuous primary endpoint summarized as a mean with a 95% confidence interval, and it describes the endpoint’s time frame and imaging contrast. It does not report an analysis model, numerical endpoint results, p-values, or a statistical analysis plan. The following concepts explain how such an endpoint is generally interpreted; they do not imply that a particular method was used in this study.

What does a mean represent?

For a continuous measure, a mean is an average of the observed values in the analysis population. Here, the endpoint description indicates a mean change in BOLD contrast. A mean can give a concise description of the group’s measured change, but it does not show the spread of individual responses. Participants may have values above and below the group average. Without the reported mean, participant-level distribution, or numerical interval, the size and variability of the measured change cannot be assessed.

What does the confidence interval communicate?

A confidence interval expresses uncertainty around an estimate under the assumptions of the method used to construct it. A narrower interval indicates greater precision than a wider interval, considered in the context of the same measure and method. It is not a guarantee that the true value lies within the observed bounds, and it does not determine whether a finding is clinically meaningful. The registry record names a 95% confidence interval, but its bounds are not reported. The interval therefore cannot be used to assess precision or whether the result is compatible with a range of possible effects.

What is the role of randomization?

Random assignment is intended to make treatment groups comparable on average, including for characteristics that may not be measured. In a small study, however, randomization does not ensure that the groups will be balanced on every characteristic. The record identifies randomized allocation but does not describe the randomization sequence, concealment, or any adjustment for baseline characteristics. The group sizes are small, so any treatment comparison would need to be read with attention to uncertainty and the specific analysis population.

How does the imaging contrast work?

The primary measure concerns BOLD signal during aggressive response relative to monetary response in the PSAP task. BOLD fMRI reflects changes in blood oxygenation associated with neural activity; it is an indirect signal rather than a direct count of neural events. The endpoint is the change in this contrast from baseline to post-treatment. The description defines a positive value as an increase in activity and states that a region of interest is characterized by the location of a peak value using MNI X, Y, Z coordinates. Without numerical results, coordinates, or a reported analysis method, the location and magnitude of any signal change are unknown.

Why can imaging results be sensitive to analysis choices?

Imaging analyses can involve choices about preprocessing, regions or voxels examined, task contrasts, and how statistical evidence is evaluated. Those choices affect what an estimate represents and how uncertainty should be understood. The registry record does not report the detailed imaging-processing pipeline, region-selection procedure, thresholding approach, or whether the primary analysis was adjusted for other factors. These details should not be inferred from the endpoint label alone.

What does multiplicity mean in this context?

Multiplicity arises when several outcomes, contrasts, time points, or analytical choices are examined. The more opportunities there are to identify an apparently unusual result, the more important it is to describe how the analyses were selected and whether any adjustment or hierarchy was used. The record lists seven outcome measures and no statistical analyses, but does not report a multiplicity strategy. It also does not provide a protocol-level account of planned versus exploratory analyses. No adjusted or unadjusted primary comparison is available to interpret.

How should planning illustrations be read?

Sample-size illustrations are planning calculations, not observed findings and not a substitute for the trial’s results. The registry record describes illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. Such calculations depend on their assumptions and cannot establish that a study had a particular probability of detecting an effect after the fact. They are not observed power. The record does not report the trial’s own sample-size justification or design assumptions, and no numerical planning estimates are reported in the available record.

More generally, over-dispersion occurs when observed variability exceeds what a statistical model assumes. If a model underestimates variability, its uncertainty estimates may be too narrow. This is a general statistical consideration, not a reported feature of this study. The registry record does not describe a model for the continuous imaging outcome, so there is no basis for saying whether over-dispersion was assessed or relevant in the analysis.

10. Multiplicity, Missing Data and Analysis Populations

The record lists seven outcome measures and reports no statistical analyses. It names the aggression-related BOLD fMRI contrast as the primary endpoint and GABA and glutamate levels using MRS as a secondary outcome, but it does not report a complete inferential analysis or numerical outcome estimates. A multiplicity adjustment, outcome hierarchy, or strategy for handling multiple contrasts and time points is not reported in the registry record. The record also does not say whether other exploratory analyses were planned or performed.

The primary endpoint’s completed population is defined as randomized participants with baseline imaging, including the anatomical scan, and post-treatment imaging. This definition clarifies which participants would qualify for that endpoint population, but the number who met the criteria is not reported. The total enrollment is 7; the number randomized to each arm for the imaging endpoint, the number with usable scans, and the number included in an analysis are not separately reported.

Handling of missing imaging data is not reported. The record does not describe whether missing scans were excluded, imputed, or handled using another method, nor does it explain how incomplete task data or unusable imaging scans would be treated. The analysis population for the secondary MRS outcome is also not reported. These omissions limit assessment of attrition, the relationship between randomization and the analyzed sample, and the potential effect of missing data on any treatment comparison.

The registry record does not report an intention-to-treat analysis, a per-protocol analysis, interim analyses, or a prespecified statistical analysis plan. Their use or absence should not be inferred. With no posted inferential results, it is not possible to judge how multiplicity or missing data affected the primary estimate.

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 serious adverse-event summary reports 0 affected participants among 4 at risk in the placebo group and 0 among 3 at risk in the high-dose SPN-810 group. The record lists 0 deaths in each group. For other adverse events, it reports 2 affected participants among 4 at risk with placebo and 1 among 3 at risk with SPN-810. These are participant counts, not a statistical comparison of risk.

The small group counts mean that each participant represents a substantial part of the posted summary. The counts should therefore be read descriptively and not as a precise estimate of how often events would occur in a larger population. They also do not establish whether an event was caused by study treatment. The registry record does not provide event terms for the other adverse events, details of severity, timing, or a treatment-relatedness assessment. No serious adverse-event terms are listed. Absence of a listed serious event in these summaries does not establish that a treatment is safe or that uncommon harms are absent.

Both groups received stable optimized ADHD medication in addition to SPN-810 or placebo, so these safety counts reflect the study’s treatment context. The record does not report a detailed safety analysis or a reason for the study’s terminated status. The status should not be interpreted as evidence of a safety concern.

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

The registry record provides a description of an exploratory randomized imaging study and a limited safety summary. It does not provide the numerical result for the primary fMRI endpoint, its stated 95% confidence interval, or an inferential comparison between SPN-810 and placebo. As a result, the posted information does not establish whether the groups differed in aggression-related BOLD change, how large any difference was, or how precisely it was estimated.

The endpoint was designed to measure change in a task-related brain signal over 4 weeks. Even if a numerical imaging result were available, it would describe the specified BOLD contrast, not by itself demonstrate a change in clinical symptoms or behavior. The registry record does not report a numerical clinical outcome that would link the imaging measure to a patient-centered treatment effect.

The adverse-event figures describe the number of affected participants recorded in each group, including no serious adverse events or deaths in either group and other adverse events in 2 placebo participants and 1 SPN-810 participant. Those counts are limited by the small enrollment and do not establish comparative safety. The record does not report event details or causal assessments.

The terminated status is a registry designation. The reason for termination is not reported in the registry record, so it cannot be attributed to efficacy, safety, feasibility, or another cause. The intended imaging analysis population is defined, but its actual size is not stated. Consequently, the available information is insufficient to assess missing-data effects or the precision of any imaging comparison.

In practical statistical terms, the record documents the question the investigators set out to study, the randomized treatment contrast, the endpoint definition, and selected safety counts. It does not supply the primary results needed to judge the magnitude, direction, or uncertainty of the treatment contrast. Neither a positive nor a negative conclusion about the primary endpoint follows from the information posted.

13. Why This Trial Matters Statistically

This trial is statistically notable because it combines a randomized treatment comparison with an exploratory neuroimaging endpoint in a small pediatric study. The primary measure is not a simple symptom score: it is a change in BOLD contrast during a behavioral provocation task, comparing aggressive response with monetary response. Understanding the estimand therefore requires attention to the task definition, the imaging signal, the time contrast, and the population with complete scans.

The study also illustrates the difference between a registered endpoint and a reported result. The endpoint description is detailed, and the record names a mean and 95% confidence interval, yet no numerical endpoint estimate or analysis is posted. Without those results, readers cannot evaluate uncertainty, between-group differences, or the role of any analysis choices. A clearly specified measure is not a substitute for a reported estimate.

The enrollment of 7 is especially relevant to interpretation. Small studies can be informative as exploratory work, but their estimates are often highly uncertain, and small participant counts provide limited ability to characterize adverse events. Here, the safety summaries are counts, while the primary imaging result is absent. It is important not to turn descriptive counts or planning illustrations into evidence about treatment effects.

Finally, the study’s terminated status and the lack of a reported reason highlight the importance of complete registry reporting. Reasons for termination, analysis populations, missing-data handling, and statistical methods all help readers judge how results should be understood. Those details are not reported in the registry record. The case underscores why statistical interpretation depends not only on design labels and endpoint definitions, but also on transparent reporting of results and analysis decisions.

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 principal trial-specific limitation in the registry record is that it does not report a numerical result for the primary imaging endpoint. Although the endpoint is defined as a mean change with a 95% confidence interval, neither the estimate nor interval bounds are posted. No primary statistical comparison or analysis is reported, so the direction, size, and precision of any treatment contrast cannot be assessed.

Enrollment was 7, and the posted adverse-event groups include 4 placebo participants and 3 high-dose SPN-810 participants. Such small group counts make descriptive safety summaries highly limited. The number of participants who completed the baseline and post-treatment imaging required for the primary endpoint is not reported. The record therefore does not establish how many participants contributed to the imaging analysis or whether scan availability differed by group.

The endpoint depends on a task-related fMRI contrast and a defined behavioral response. Details of image processing, region selection, statistical thresholds, handling of unusable scans, and the analysis model are not reported. These omissions prevent a full assessment of how the imaging signal was derived and how robust an estimate might be to analytical choices. The record also lists seven outcome measures without describing a multiplicity strategy.

The reason for termination, the trial’s planned enrollment, and its sample-size justification are not reported. The posted sample-size assumptions describe planning illustrations rather than the trial’s own design justification, and no numerical illustration results are available in the registry record. The record does not report an interim-analysis plan, a detailed missing-data approach, or a statistical analysis plan. These limits should be kept distinct from evidence of a particular outcome: the missing details do not establish that the study had a biased result or that termination reflected a specific concern.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD — NCT03638466.
• Registry record last updated 2025-05-02; status last verified 2025-02.
• Results first posted 2025-05-02.
• 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

NCT03638466 is a terminated phase 2 randomized, quadruple-masked, parallel-group study of SPN-810 for impulsive aggression in children aged 8-12 years with ADHD. The registry record reports enrollment of 7 and a study period from 2019-05-30 to the primary completion date of 2019-11-07. Participants were assigned to high-dose SPN-810 or placebo in addition to stable optimized ADHD medication.

The primary endpoint was change in aggression-related whole-brain BOLD fMRI contrast during the PSAP task over 4 weeks. The record describes a mean and 95% confidence interval but does not report a numerical endpoint result or statistical analysis. Serious adverse events and deaths were reported for 0 participants in both groups; other adverse events were reported for 2 placebo participants and 1 SPN-810 participant. The reason for termination, actual imaging analysis population, and detailed statistical methods are not reported in the registry record.