Study of Flexible Doses of the Triple Reuptake Inhibitor EB-1020 Sustained Release (SR) in the Treatment of Adult Males With Attention-Deficit Hyperactivity Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Flexible Doses of the Triple Reuptake Inhibitor EB-1020 Sustained Release (SR) in the Treatment of Adult Males With Attention-Deficit Hyperactivity Disorder (NCT01939353), a na phase 2 study. The primary outcome is Change From Baseline-2 in ADHD Symptoms to Week 4 as Assessed by the Adult Attention-Deficit Hyperactivity Disorder Rating Scale (AD HD-RS-IV).

2. Clinical Question

The study was an exploratory Phase 2 pilot trial of flexible doses in adult males with ADHD. Its stated aims included evaluating an effectiveness signal and safety, and exploring dosing, tolerability, onset of action, duration of effect, and dose-response/tolerability relationships. Those aims describe what the investigators set out to examine; without numerical outcome results, they do not establish the size or direction of any observed symptom change.

The design is important to the question. A change measured during treatment can describe what happened in the treated group, but a single-group study cannot by itself separate a treatment-associated change from changes that might occur over time or through other influences. The placebo run-in does not supply a randomized concurrent comparison. The registry record therefore supports describing the planned assessment and study structure, but not a comparative estimate of treatment effect.

3. Trial Design

This was a completed, exploratory, single-blind Phase 2 pilot trial with a single-group model. The registry lists enrollment as 45. The study start date was 2013-10-03 and the primary completion date was 2014-02-20. The registry lists adult ADHD as the condition and Otsuka Pharmaceutical Development & Commercialization, Inc. as the sponsor.

Participants first underwent a 1-week single-blind placebo run-in. The registry says the run-in was also used for informal safety comparison purposes. After the run-in, participants with less than 30% improvement and an Adult ADHD-RS-IV total score of at least 28 received centanafadine sustained release. The treatment arm is titled Centanafadine SR 100-500 mg. The record describes flexible dosing, but the available arm description is incomplete, so the full dosing sequence is not reported in the registry record.

Single-blind means masking was listed as single; the registry information does not identify who was masked. Allocation is listed as not applicable, and the model is single-group. Consequently, the placebo run-in should not be interpreted as a randomized placebo arm that remained alongside treatment for a concurrent comparison. The record explicitly cautions that this was not a randomized comparison and that arms are not a like-for-like control comparison.

The study included 4 weeks of drug treatment. The primary outcome was assessed from Baseline-2 to Week 4, with Baseline-2 defined at the end of the run-in and beginning of CTN SR treatment. The primary endpoint population was per protocol, not simply everyone enrolled: it included participants meeting eligibility criteria who completed treatment with evaluable data after Week 4 and without major protocol violations.

The registry record does not report a rationale for the planned enrollment, a formal sample-size justification, or a detailed statistical analysis plan. The study's exploratory aims and single-group structure should therefore guide interpretation; additional design details should not be assumed.

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: A total of 45 male participants diagnosed with attention-deficit hyperactivity disorder (ADHD) were enrolled at Baseline-1 in a 1-week single-blind (SB) placebo run-in treatment to receive placebo from Baseline-1 to Baseline-2. At Baseline-2, remaining 41 out of 45 participants who had \<30% improvement and ≥28 total score on Adult ADHD-RS-IV scale score received centanafadine (CTN) sustained release (SR) 100-500 mg, tablets from Week 1 to Week 4.

Placebo Run-in (1 Week)

Reasons for not completing this period:

CTN SR Treatment Phase (4 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per-protocol Population included all participants who met inclusion/exclusion criteria and completed the trial (4 weeks of drug treatment with evaluable data after Week 4) without major protocol violations.

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: Safety Population included all participants who received at least 1 dose of CTN SR (not placebo) as indicated in the treatment regimen.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline-2 in ADHD Symptoms to Week 4 as Assessed by the Adult Attention-Deficit Hyperactivity Disorder Rating Scale (AD HD-RS-IV), measured over Baseline, Week 4.

The primary endpoint was change from Baseline-2 to Week 4 in ADHD symptoms, assessed with the Adult ADHD-RS-IV. The scale has 18 items: the first 9 assess inattentive symptoms and the last 9 assess hyperactive-impulsive symptoms. Each item uses a 4-point Likert-type severity scale scored from 0 (none) to 3 (severe), and the total score ranges from 0 to 54. The registry specifies that a negative change from Baseline-2 indicates improvement.

A symptom rating scale provides a structured way to summarize symptom severity across the domains named in the instrument. Measuring change uses each participant's Baseline-2 assessment as the reference point for the later assessment. In general, a mean change summarizes the average direction and magnitude of change in the analyzed population; it does not show whether every participant changed in the same way.

Baseline-2 is a specific reference point in this study, not an unspecified pre-study assessment: it was taken at the end of the 1-week single-blind placebo run-in and at the beginning of CTN SR treatment. The endpoint therefore concerns change after treatment began relative to that point. The registry gives the endpoint definition and the per-protocol population, but the numerical mean change, its standard deviation, and any confidence interval or test result are not reported in the registry record. The endpoint's direction and precision cannot be assessed from its definition alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change describe?

General statistical explanation: For a continuous outcome, a mean change summarizes the average difference between a participant's later measurement and the chosen baseline measurement across the analyzed group. It can describe the group's average trajectory, but it does not imply that each participant experienced that average change. The Adult ADHD-RS-IV is a continuous score, and the registry specifies the mean as the parameter for the primary outcome, with standard deviation as the dispersion measure.

The interpretation depends on the baseline definition. In this trial, Baseline-2 is the end of the placebo run-in and start of treatment, and the follow-up assessment is at Week 4. The registry says that negative change indicates improvement. This sign convention tells a reader how to read an estimate if one is reported; it does not indicate the actual result. The mean change and standard deviation are not reported in the registry record.

What does a standard deviation add?

General statistical explanation: A standard deviation describes the spread of participant measurements around the group mean. It is not the same as a confidence interval and does not, on its own, express how precisely the mean has been estimated. A confidence interval uses information about the estimate and its uncertainty to give a range of values compatible with the data under the analysis assumptions. Neither the primary endpoint's standard deviation nor a confidence interval is reported in the registry record, so the precision of the estimated change cannot be evaluated from the endpoint description.

Why does the study design affect the estimate?

General statistical explanation: In a randomized controlled comparison, random allocation is intended to make groups comparable on average, allowing a between-group contrast to estimate the difference associated with assignment, subject to the study's assumptions and conduct. A single-group before-and-after assessment instead describes change in one group. Other influences, including natural change over time, expectations, and measurement variation, can contribute to a before-and-after difference. These general considerations do not establish that any particular influence occurred in this trial.

The registry classifies this study as single-group, lists allocation as not applicable, and says it was not a randomized comparison. The single-blind placebo run-in preceded CTN SR treatment and had an informal safety-comparison purpose. It does not create a concurrent randomized comparator for the primary efficacy question. Thus, even a reported within-group change would not have the same interpretation as a randomized between-group treatment contrast.

What does the per-protocol population mean?

The primary endpoint population included participants who met inclusion and exclusion criteria, completed 4 weeks of drug treatment with evaluable data after Week 4, and had no major protocol violations. This definition focuses the analysis on participants meeting those stated conditions. General statistical explanation: restricting an analysis population can affect how representative its estimate is of everyone who enrolled or might be treated. A per-protocol result should therefore be read as an estimate for the defined analysis population, not automatically as a result for all enrolled participants.

The number of participants in the primary endpoint population is not reported in the registry record. The enrollment count of 45 does not supply that denominator, because the endpoint population has additional completion and evaluability criteria. The safety group lists 41 at risk, but that is a safety denominator and should not be substituted for the primary endpoint population size.

What can a p-value or confidence interval establish?

General statistical explanation: A p-value describes how incompatible the observed data are with a specified statistical null model, under the assumptions of the analysis. It is not the probability that the null hypothesis is true and does not measure the size or clinical importance of an effect. A confidence interval conveys uncertainty about an estimate and is useful for judging which effect sizes are compatible with the data and model. Neither type of result is reported for the primary endpoint in the registry record. No test result or interval should be inferred from the endpoint's stated scale or design.

How should planning illustrations be distinguished from trial results?

General statistical explanation: A sample-size planning illustration describes how many participants might be needed under specified assumptions to detect a chosen effect with a chosen design and error rate. It is not a count of observed participants, an observed effect, or evidence that a study had a particular probability of success. The registry's stated planning assumptions describe a hypothetical calculation using an observed effect, equal allocation between two arms, a normal approximation, and a two-sided significance level of 0.05. Those assumptions do not describe the actual single-group study design, and the planning illustration is not the trial's own design justification. The record does not report a formal sample-size justification for this pilot trial.

These distinctions are especially important for a study whose primary numerical result is not reported in the registry record. Without an observed endpoint estimate and its uncertainty, no effect-based planning interpretation can substitute for the missing outcome result. The statistical methods information can clarify what was intended to be measured, but it cannot recover an unreported estimate.

Why can dispersion matter?

General statistical explanation: Participants can vary in their scores and in how their scores change. Greater dispersion makes a group mean less representative of any one participant and can make the mean harder to estimate precisely, depending on the analysis and amount of data. Reporting both a mean and a measure of spread helps readers understand the distributional context of an average. The registry names standard deviation for dispersion but does not report the primary endpoint's numerical standard deviation. No further distributional properties or analysis details are reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, including the primary Adult ADHD-RS-IV change outcome and secondary measures addressing ADHD symptoms, executive function, responder status, subscales, and clinical global impression. When several outcomes or analyses are considered, the chance of at least one apparently notable result can increase if each is assessed separately. General statistical explanation: multiplicity procedures can address this issue by controlling a chosen error rate or by defining a hierarchy of outcomes and tests.

The registry record does not report a multiplicity adjustment, a testing hierarchy, or a detailed statistical analysis plan. It lists 0 analyses in the analysis information. This means that the registry information does not provide analysis entries from which to determine how outcomes were modeled, how comparisons were handled, or whether any multiplicity strategy was used. The absence of a reported strategy is not evidence that a particular strategy was or was not applied outside the registry record.

Missing-data handling is also not reported in the registry record. The primary endpoint population requires evaluable data after Week 4, but the record does not describe how participants without such data were handled, whether data were imputed, or what sensitivity analyses were performed. The per-protocol definition indicates that completion and evaluability were conditions for inclusion in that population; it does not give the number excluded or explain the reasons for missing assessments.

The record does not report a formal sample-size justification or detailed assumptions used to determine enrollment. A planning illustration based on an observed effect is distinct from the trial's own design rationale and is not evidence of observed power. These omissions limit assessment of the planned inferential approach and the robustness of any outcome interpretation.

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: cerebrovascular accident (2.4%).

The safety figures list 41 participants at risk in the Centanafadine SR 100-500 mg group. The record reports 1 participant with a serious adverse event, 34 participants with other adverse events, and 0 deaths. It also lists cerebrovascular accident at 2.4% among the top serious adverse event terms. These are separate registry entries: the serious-event count is a participant count, while 2.4% is the percentage attached to the listed term.

General statistical explanation: A count of participants with an event is not the same as a count of all event episodes; a participant can experience more than one event. The registry figures should therefore be read according to their labels and not treated as a complete description of event timing, duration, severity, or relationship to treatment. Those additional details are not reported in the registry record.

The safety figures are descriptive. Because the study was single-group and the placebo run-in served an informal safety-comparison purpose, these counts do not provide a randomized comparison of safety between treatments. The 41 at-risk participants are the denominator for the listed safety group, not necessarily the denominator for the primary efficacy analysis. The registry record does not provide a detailed safety analysis plan or additional context for the listed serious-event term.

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

The registry record establishes that the study examined flexible-dose centanafadine sustained release in adult males with ADHD and defined a primary symptom outcome: change in Adult ADHD-RS-IV score from Baseline-2 to Week 4. It specifies that a negative change indicates improvement and defines the per-protocol population. These details explain the intended question and how a numerical result would be read.

The numerical primary outcome result is not reported in the registry record. As a result, the record does not establish the average amount or direction of symptom change, nor how precisely that change was estimated. The study's stated aims to evaluate an effectiveness signal and explore tolerability, dosing, onset, duration, and dose-response relationships should not be mistaken for reported findings on those questions.

The single-group design also limits what a change over time could establish. General statistical explanation: An observed before-and-after change can be consistent with a treatment effect, but without a concurrent randomized comparator it cannot isolate treatment as the cause of that change. The registry explicitly identifies the study as not a randomized comparison. The placebo run-in was not described as a concurrent randomized efficacy control.

The enrollment count of 45 describes the study enrollment, while the primary endpoint applies to a narrower per-protocol population. The size of that population is not reported in the registry record. The safety figures describe a group of 41 at risk and should not be taken as the primary endpoint denominator.

Accordingly, the posted registry information supports a description of the study's design, outcome definitions, and selected safety counts. It does not support a quantitative conclusion about the primary symptom result or a causal comparison with placebo. The absence of a numerical result is an important reporting limitation, not evidence that the outcome was unchanged or that the study failed to detect a difference.

13. Why This Trial Matters Statistically

This trial is statistically instructive because its question, design, and analysis population need to be considered together. The Adult ADHD-RS-IV endpoint is defined as a continuous score change from a clearly specified Baseline-2 to Week 4. The record states the scale structure and identifies negative change as improvement. Those definitions make the intended outcome interpretable, but they cannot replace the numerical estimate needed to understand what was observed.

The single-group design highlights the difference between measuring change and estimating a comparative treatment effect. A within-group change can describe the course of scores in participants receiving treatment. A randomized comparison is designed to support a different inference by comparing outcomes across allocated groups. The registry identifies this study as nonrandomized and says its arms are not a like-for-like control comparison. The placebo run-in had an informal safety purpose, not a concurrent randomized efficacy-control role.

The per-protocol population definition is another important feature. It requires eligibility, completion of treatment, evaluable post-treatment data, and no major protocol violations. That definition makes clear that the primary endpoint does not necessarily represent every enrolled participant. Because the size of this population and the handling of missing data are not reported in the registry record, readers cannot assess the effect of those criteria on the result.

Finally, the record lists multiple outcomes but does not report a detailed analysis plan or multiplicity approach. This matters because interpretation depends not only on the outcome definitions but also on which analyses were planned and how uncertainty was handled. The trial is therefore a useful example of why transparent reporting of estimates, precision, analysis populations, and methods is necessary for evaluating an exploratory study. Its registry description supplies a clear outline of the intended measurement, but the absence of primary numerical results prevents a statistical assessment of the observed symptom change.

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 central limitation for interpreting the primary endpoint is that its numerical result is not reported in the registry record. Although the scale, time points, direction of improvement, and analysis population are defined, the mean change and its variability are unavailable. The magnitude and precision of the primary outcome therefore cannot be evaluated from the registry information.

The single-group model and absence of random allocation limit causal interpretation. The placebo run-in was single-blind and was used for informal safety comparison purposes; the registry does not describe it as a concurrent randomized control. The study consequently does not provide a like-for-like randomized comparison for the primary symptom outcome.

The study population and analysis population are also distinct. The registry lists enrollment as 45, but defines the primary population by eligibility, completion, evaluable data after Week 4, and absence of major protocol violations. The number meeting that definition is not reported in the registry record. Missing-data procedures, reasons for missing assessments, and sensitivity analyses are likewise not reported.

The registry lists 14 outcome measures but does not report a detailed statistical analysis plan, multiplicity strategy, or analysis entries. The intended methods for handling multiple outcomes and drawing inferences are therefore unclear from the registry record. A formal sample-size justification is not reported, and the planning assumptions described in the record should not be treated as the trial's own design rationale.

Other limits include the exploratory pilot context and the restricted population of adult males with ADHD. The arm description is incomplete, so the full flexible-dose schedule is not reported in the registry record. These limitations do not establish that a particular bias or problem occurred; they identify what the posted registry information does not permit readers to assess.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Flexible Doses of the Triple Reuptake Inhibitor EB-1020 Sustained Release (SR) in the Treatment of Adult Males With Attention-Deficit Hyperactivity Disorder — NCT01939353.
• Registry record last updated 2026-05-19; status last verified 2026-05.
• Results first posted 2021-10-18.
• 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

NCT01939353 is a completed Phase 2 exploratory, single-blind, single-group pilot trial sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. It enrolled 45 adult males with ADHD and examined flexible-dose centanafadine sustained release after a 1-week single-blind placebo run-in. The listed study dates are 2013-10-03 for the start and 2014-02-20 for primary completion.

The primary outcome was change from Baseline-2 to Week 4 in Adult ADHD-RS-IV score. Negative change was defined as improvement. The primary population was per protocol, requiring eligibility, completion of 4 weeks of drug treatment with evaluable data after Week 4, and no major protocol violations. The numerical primary result and its precision are not reported in the registry record.

The registry lists 14 outcome measures and safety figures of 1 serious adverse event, 34 participants with other adverse events, and 0 deaths among 41 at risk in the centanafadine group. The study was not a randomized comparison, and the placebo run-in was intended for informal safety comparison purposes. Missing-data methods, multiplicity handling, and a formal sample-size justification are not reported in the registry record.