Open-label, Single-dose Trial to Assess the Pharmacokinetics of Centanafadine Extended-release Capsules in Pediatric Participants With Attention-deficit Hyperactivity Disorder (ADHD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Open-label, Single-dose Trial to Assess the Pharmacokinetics of Centanafadine Extended-release Capsules in Pediatric Participants With Attention-deficit Hyperactivity Disorder (ADHD) (NCT04081363), a na phase 2 study. The primary outcome is Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of Centanafadine.

2. Clinical Question

The trial was designed to characterize pharmacokinetics, or PK: how drug concentrations in the body change over time after administration. The registry description explains that pediatric PK may differ from adult PK because of physiological differences in the gastrointestinal tract. It states that the information was intended to support dose selection in future pediatric trials. That rationale concerns future research planning, rather than a comparison of clinical benefit.

The two administration cohorts are described as swallowed capsules and capsule contents sprinkled onto applesauce. Both received a stated total dose of 55 mg orally in the morning of Day 1 following a minimum 8-hour fast. The record does not report a randomized assignment process, a placebo group, or a separate active comparator. The trial therefore addresses concentration after dosing, not whether centanafadine is more effective than another treatment or than no treatment.

The primary outcome is a pharmacokinetic measure, not a symptom or functional outcome. The registry record does not report numerical Cmax results, so the magnitude and precision of the observed concentration cannot be described from the posted results.

3. Trial Design

This was a completed Phase 2a, multicenter, open-label, single-dose trial. The registry record lists a single-group model, no masking, and allocation as not applicable. Enrollment was 13. The trial start date is 2019-10-07 and the primary completion date is 2019-12-21. These design features describe a small pharmacokinetic study rather than a randomized treatment comparison.

Participants received a single oral dose of centanafadine. In the Swallowed Capsules Cohort, the dose was two capsules: one containing 50 mg as extended-release beads and the other containing 5 mg as immediate-release beads, for a total dose of 55 mg. In the Sprinkled Onto Applesauce Cohort, the contents of two capsules containing the same stated components were sprinkled on a tablespoon of applesauce, for a total dose of 55 mg. Both descriptions specify administration in the morning of Day 1 following a minimum 8-hour fast.

The cohort descriptions distinguish administration format, but the record does not report random assignment or a statistical comparison between cohorts. Accordingly, a difference between cohort values, if such values were available, would not by itself establish that the administration formats caused different concentrations. The record does not report the rationale for assigning participants to a cohort, nor does it describe a control group.

The primary outcome concerns maximum plasma concentration after dosing. Concentration assessments were scheduled at 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose on Day 1 and 22-26 hours post dose on Day 2. The PK analysis set included participants who received the single dose and had at least 1 postdose evaluable plasma concentration. The registry record does not report the number included in that analysis set or the numerical outcome values.

The study is marked completed. Completion status does not establish that every planned analysis or outcome result is present in the registry record. The registry record does not report a detailed statistical analysis plan, a sample-size justification, or interim 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.

Before assignment: A total of 20 participants were screened and 13 participants were enrolled in the study to receive centanafadine as capsules or sprinkled onto applesauce.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) analysis set included all participants who received the single dose of centanafadine and had at least 1 postdose evaluable plasma concentration.

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: Enrolled analysis set included all participants who had eligibility to enroll in the trial based on screening process.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetic (PK) Parameter: Maximum Plasma Concentration (Cmax) of Centanafadine, measured over 1, 2, 3, 4, 6, 8, 10,12 hours post dose on Day 1 and 22-26 hours post dose on Day 2.

The primary endpoint is the maximum plasma concentration of centanafadine, called Cmax, measured in nanograms per milliliter. It is a continuous pharmacokinetic measure: it describes the highest measured plasma concentration after a dose. The listed summary measure is the mean, with standard deviation as the measure of dispersion.

Concentration measurements were scheduled at 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose on Day 1 and 22-26 hours post dose on Day 2. Sampling at multiple times is relevant because a maximum concentration is identified from observations over time; it is not the same as a single measurement at a fixed time. The registry record does not report the actual Cmax mean or standard deviation, nor does it report participant-level concentration values or the number contributing to the PK analysis set.

General statistical context: Cmax is used to characterize peak systemic exposure. It can describe the concentration profile following administration, but by itself it does not measure symptom change, functional improvement, or comparative clinical benefit. The Cmax endpoint is suited to a PK objective because the study asks about drug concentration after a single dose. Its interpretation depends on the timing and completeness of concentration measurements, along with how the endpoint is summarized.

Because the numerical endpoint results are not reported in the registry record, the posted information does not establish the average peak concentration or how much participants' values varied. The stated endpoint and sampling schedule explain what the study set out to measure, but do not supply the result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical context: A continuous outcome can be summarized by its mean, which describes the arithmetic center of observed values, and its standard deviation, which describes their spread around the mean. The registry record specifies mean and standard deviation for Cmax. It does not provide either numerical summary. Without those values, readers cannot judge the observed level of Cmax or the variation among participants.

What does Cmax represent?

Cmax is the maximum plasma concentration observed after a dose. It is a PK endpoint: the measurements concern drug concentration over time rather than a clinical response. The study lists scheduled collection times on Day 1 and Day 2, but the registry record does not provide the concentrations at those times or explain the specific rule used to derive the maximum from available measurements. In general, the value identified as a maximum depends on what was measured and when; sparse or missing measurements can affect how well a peak is characterized.

What can a mean and standard deviation tell a reader?

General statistical context: The mean offers a summary of the group center, while the standard deviation communicates how dispersed observations are. These summaries do not show the full distribution. The mean can be affected by unusually high or low values, and the standard deviation does not indicate the uncertainty in the mean in the same way that a confidence interval does. A confidence interval, in general, describes a range of values compatible with the data and a specified statistical procedure. No confidence interval for Cmax is reported in the registry record, so the precision of the mean cannot be evaluated from the posted results.

Why does the study design matter?

This was an open-label, single-dose study with a single-group model and allocation marked not applicable. In general, open-label means treatment administration is not masked from participants or study personnel. A study without randomized assignment to a control group does not provide the same basis for separating treatment effects from other differences as a randomized controlled comparison. In this trial, the two cohort descriptions distinguish how the dose was taken, but the record does not report that participants were randomly assigned between those formats. The record also does not state a formal between-cohort analysis.

The single-dose design is aligned with a PK question about concentrations after administration. It does not, on its own, answer questions about repeated dosing, longer-term exposure, symptom outcomes, or comparative effectiveness. Those issues are not reported as endpoints in the registry record described for this analysis.

How should the analysis population be understood?

The registry record defines the PK analysis set as all participants who received the single dose and had at least 1 postdose evaluable plasma concentration. This is a stated eligibility rule for the analysis population, but the number who met the rule is not reported in the registry record. The number enrolled is 13, and that enrollment count should not be taken as the number analyzed for Cmax without an explicit analysis-set count.

General statistical context: When eligibility for an analysis set depends on having evaluable postdose measurements, incomplete follow-up or unevaluable samples can affect who contributes to the estimate. If the participants with missing measurements differ systematically from those with complete measurements, the analyzed group may not represent everyone enrolled. The registry record does not describe missing concentration data, reasons for unevaluable samples, or any method for handling missing values. It is therefore not possible to assess the consequences of missing data for the reported outcome.

What do planning calculations mean?

General statistical context: A sample-size calculation is a planning exercise about the amount of information a future study may need under stated assumptions. It is not a measure of the probability that a completed study has demonstrated an effect. The registry record describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the target effect is expressed as a fraction of the observed effect. It also distinguishes participants per arm for non-time-to-event outcomes from total events for time-to-event outcomes.

Those assumptions are not the same as the design of this trial, which is listed as a single-group, nonrandomized study. Numerical planning results and the observed effect used for any such illustration are not reported in the registry record. Consequently, those calculations cannot be used as evidence that the trial had adequate power, and they should not be described as observed power. The registry record does not report a sample-size justification for the trial's own design.

The registry record lists 3 outcome measures and 0 analyses. It does not report the statistical analysis plan, any interim analyses, or a multiplicity procedure. General methods such as adjustment for multiple comparisons can affect the interpretation of inferential results when several outcomes or tests are examined, but no adjustment or test results can be attributed to this trial based on the registry record.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Swallowed Capsules Cohort", "Sprinkled Onto Applesauce Cohort")
n   <- c(6, 6)
m   <- c(153, 129)
sp  <- c(51.4, 52.8)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Swallowed Capsules Cohort  6  153.000  51.400  99.059  206.941
CARM  Sprinkled Onto Applesauce Cohort  6  129.000  52.800  73.590  184.410

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 3 outcome measures and 0 analyses. It identifies Cmax as the primary outcome, but does not report numerical results for that endpoint or provide results for the other outcome measures. A statistical analysis plan, multiplicity adjustment, and interim analyses are not reported in the registry record. It is therefore not possible to determine which statistical procedures were prespecified, whether more than one inferential test was conducted, or how any multiplicity was handled.

General statistical context: When several outcomes or statistical tests are considered, the chance of obtaining a seemingly notable result by chance can change. Procedures for controlling multiplicity may be used to address that issue. The relevance of such procedures depends on the outcomes, hypotheses, and analyses planned and conducted. Because those details are not reported in the registry record, no claim can be made about whether adjustment was needed or applied.

The PK analysis set is defined as participants who received the single dose and had at least 1 postdose evaluable plasma concentration. The record does not report the number in that set, the number with missing or unevaluable measurements, the reasons for missingness, or the handling of incomplete concentration profiles. No imputation procedure or other missing-data method is reported in the registry record. The extent to which the analysis population differed from the enrolled population therefore cannot be assessed.

The listed endpoint summary is a mean and standard deviation. The registry record does not state how the analysis accounted for the timing of measurements, whether any covariates were considered, or how concentration values below a measurement limit, if any, were treated. These details are not reported in the registry record and should not be inferred from the endpoint description alone.

12. 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 safety figures are reported separately for the Swallowed Capsules Cohort and the Sprinkled Onto Applesauce Cohort. For serious adverse events, 0 of 7 participants at risk were affected in the swallowed-capsules cohort, and 0 of 6 were affected in the applesauce cohort. The registry record reports 0 deaths in each cohort. It lists no top serious adverse event terms.

For other adverse events, 1 of 7 participants at risk was affected in the swallowed-capsules cohort, and 0 of 6 participants at risk were affected in the applesauce cohort. These are participant counts, not event rates calculated from the data. The record does not provide further details about the event reported in the swallowed-capsules cohort, such as its nature, timing, severity, or relationship to treatment.

General statistical context: A zero count means no event of that category was recorded among the stated participants at risk; it does not establish that the event cannot occur. Small cohorts provide limited information about uncommon events, and a single-dose study does not characterize longer-term exposure. Because the cohorts were not described as a randomized comparison, their safety counts should not be read as evidence that one administration format is safer than the other.

The registry record does not report a comparative statistical analysis of adverse events. These counts are descriptive observations from the trial and do not establish causation.

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

The registry record establishes that this completed study was intended to characterize centanafadine pharmacokinetics after a single oral dose in pediatric participants with ADHD. It describes two administration formats, a scheduled concentration-sampling period, and Cmax as the primary endpoint. It also defines the PK analysis set. These details clarify the study question and the kind of evidence it was designed to collect.

However, the numerical Cmax results are not reported in the registry record. Without the mean, standard deviation, or other concentration summaries, the posted results do not show the observed average peak concentration or its variability. Without an interval estimate or a reported analysis, the precision of an endpoint estimate cannot be assessed. The available registry information therefore does not support a quantitative conclusion about the PK result.

The study is not described as a randomized comparison. The swallowed-capsules and applesauce cohorts used different administration formats, but the registry record lists a single-group model and allocation as not applicable. The record does not report a control group or a formal comparison between these cohorts. The design cannot by itself establish that any difference between cohort observations is caused by the administration format.

The trial's purpose, as stated in the registry record, was to support pediatric dose selection in future trials. That purpose should not be confused with evidence that a particular dose is optimal or that centanafadine changes ADHD symptoms. The primary outcome is a concentration measure, not a clinical efficacy outcome, and numerical results for that concentration measure are not reported in the registry record.

The safety counts describe events recorded in the study, including zero serious adverse events and zero deaths in each cohort, with other adverse events affecting 1 participant in the swallowed-capsules cohort and 0 in the applesauce cohort. These observations do not demonstrate absence of risk, establish a comparative safety difference, or characterize longer-term safety.

14. Why This Trial Matters Statistically

Pharmacokinetic studies provide information about drug concentrations after administration. In pediatric research, such information can help investigators plan later studies, particularly when the registry record identifies a reason to examine whether drug handling may differ between children and adults. This trial's stated aim was to generate information to support dose selection in future pediatric trials.

The design also illustrates why the study question and the endpoint need to be read together. A single-dose concentration study can address a PK question, such as the maximum plasma concentration after administration. It does not directly answer whether symptoms improve, how a treatment compares with another option, or what happens during longer-term use. Those are different questions requiring appropriate outcomes and designs.

The two administration formats are relevant to how the dose was taken: participants either swallowed capsules or took capsule contents sprinkled onto applesauce. But the registry record does not describe random assignment or a control comparison between these groups. The cohort descriptions therefore provide context for administration, not a basis for assuming a causal comparison.

The missing numerical primary outcome is important for statistical interpretation. A stated endpoint and sampling schedule describe the intended measurement, but readers need the actual estimate and information about its variability and precision to assess the observed PK profile. Since the numerical Cmax results are not reported in the registry record, the intended contribution to future dose selection cannot be judged from these posted results alone.

The trial also shows the distinction between enrollment and an analysis population. Although 13 participants were enrolled, the PK analysis set is defined by dose receipt and an evaluable postdose concentration. The number meeting that definition is not reported. Clear reporting of analyzed participants, missing measurements, and endpoint estimates is needed to understand how the collected data support a conclusion.

15. 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 most direct limitation of the posted results is that numerical findings for the primary Cmax endpoint are not reported in the registry record. The record states the summary measure and sampling schedule, but gives no mean, standard deviation, confidence interval, or analysis result for Cmax. Readers therefore cannot assess the observed concentration level, variability, or precision.

The study enrolled 13 participants and has no randomized control group. Its open-label, single-dose, single-group design is appropriate to describe the stated PK objective, but does not support a controlled treatment-effect comparison. The two administration cohorts are not described as randomly assigned, and the registry record does not report a formal comparison between them.

The registry record defines the PK analysis set but does not state how many participants were included. It does not report the extent or reasons for missing or unevaluable plasma concentrations, or how incomplete profiles were handled. The impact of missing data on Cmax therefore cannot be assessed. It is also not reported whether the observed sampling adequately captured each participant's true peak concentration.

The listed endpoint is pharmacokinetic, not a clinical measure of ADHD symptoms or functioning. The single-dose design also does not report evidence about repeated administration or longer-term outcomes. These limitations do not change the stated purpose of the trial, but they set boundaries on what its design and registry results can address.

The registry record does not report a detailed statistical analysis plan, sample-size justification for this study, interim analyses, or a multiplicity procedure. The planning assumptions described for illustrations do not substitute for a trial-specific design justification or observed endpoint results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Open-label, Single-dose Trial to Assess the Pharmacokinetics of Centanafadine Extended-release Capsules in Pediatric Participants With Attention-deficit Hyperactivity Disorder (ADHD) — NCT04081363.
• Registry record last updated 2023-01-13; status last verified 2022-12.
• Results first posted 2023-01-13.
• 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.

19. Record Summary

NCT04081363 is a completed, multicenter, open-label, single-dose Phase 2a trial of centanafadine in pediatric participants aged 9 to 12 years, inclusive, with ADHD. The registry record reports 13 enrolled participants and describes swallowed-capsules and applesauce administration cohorts. Each received a stated total dose of 55 mg orally in the morning of Day 1 following a minimum 8-hour fast.

The primary endpoint was maximum plasma concentration of centanafadine, summarized by mean and standard deviation. Concentrations were scheduled at multiple times on Day 1 and at 22-26 hours post dose on Day 2. The PK analysis set required dose receipt and at least 1 postdose evaluable plasma concentration.

Numerical primary endpoint results and the size of the PK analysis set are not reported in the registry record. The record reports no serious adverse events or deaths in either cohort; other adverse events affected 1 participant in the swallowed-capsules cohort and 0 in the applesauce cohort. The design is descriptive and does not provide a randomized comparison.