Efficacy and Safety of SPN-812 (Viloxazine Extended-release Capsule) in Children With ADHD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of SPN-812 (Viloxazine Extended-release Capsule) in Children With ADHD (NCT02633527), a randomized phase 2 study. The primary outcome is The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV).

2. Clinical Question

The study was designed to assess efficacy and safety across several doses rather than to compare only one dose with placebo. The registry record describes a randomized, double-blind, placebo-controlled, multicenter, parallel-group study. It lists 222 participants enrolled and identifies the study as Phase 2. The primary outcome was a change score, so interpretation concerns the average movement in symptom ratings over the study period and the contrast between each dose group and placebo.

The clinical question is specific to the enrolled age range, the study duration, and the recorded scale. It does not directly address longer-term outcomes, other age groups, or outcomes beyond those listed in the registry record. The registry record does not report the original design assumptions or a rationale for selecting the number of participants.

3. Trial Design

The registry record describes a completed, randomized, quadruple-masked, parallel-group Phase 2 study of SPN-812, also called viloxazine extended-release capsule, in children with ADHD. The study was multicenter and placebo-controlled, with five groups: placebo and four active-dose groups. Each group received a once-daily oral capsule. The active doses were 100mg, 200mg, 300mg, and 400mg.

The study enrolled 222 participants. The primary endpoint was assessed from baseline to Week 8, identified as the end of the study. The primary analysis population was the Intent-to-Treat population as defined in the registry record: participants had to be randomized, take at least one dose, have a baseline ADHD-RS-IV assessment, and have at least one post-baseline assessment. Endpoint-specific group counts differ from the total enrollment; the reason for that difference is not reported in the registry record.

The primary outcome was continuous, reported as a mean change and standard deviation. The registry record also lists two continuous secondary outcomes: the Clinical Global Impression-Improvement scale at Week 8 and the Clinical Global Impression-Severity scale from baseline to Week 8. Although three outcome measures and twelve analyses are listed in the record, results are posted for the primary outcome and two secondary outcomes. The details of the other analyses are not reported in the registry record.

Randomization and masking are design features intended to reduce systematic differences between groups and reduce the influence of expectations on treatment and assessment. Those features do not, by themselves, resolve questions about missing data, multiplicity, or the choice of analysis. The allocation method, masking procedures, and trial-specific statistical plan are not reported in the registry record.

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: Intent-to-Treat (ITT) Population: The ITT population includes subjects who were randomized, took at least one dose of study medication, have a baseline Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) assessment and have at least one post-baseline ADHD-RS-IV assessment

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: Intent-to-Treat (ITT) Population: The ITT population includes subjects who were randomized, took at least one dose of study medication, have a baseline Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) assessment, and have at least one post-baseline ADHD-RS-IV assessment.

6. Primary Endpoint

The registry lists the primary outcome as The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV), measured over Baseline to Week 8 (End of Study).

The primary endpoint was change from baseline in the ADHD Rating Scale, 4th Edition, Total score at Week 8. The ADHD-RS-IV is an ADHD-specific rating scale intended to assess current symptoms. Its 18 items correspond to the 18 DSM-IV symptoms of ADHD, and each item is rated on a four-point scale from 0, “never or rarely,” to 3, “very often.” Adding item responses produces a Total score from 0 to 54, with higher scores indicating more severe ADHD symptoms.

The study analyzed the change in that total score rather than only the score at one visit. A change score captures how the average rating moved between baseline and the end of the study. The registry record states that lower changes, including changes below zero, represent a better outcome. The primary endpoint therefore provides a quantitative measure of symptom-score change over the recorded study interval.

Continuous scores can preserve more information about differences in degree than a simple yes-or-no outcome. Reporting the mean and standard deviation describes the average change and the spread of individual scores around that average. Neither statistic describes every participant’s experience, and a group mean does not show how many participants had a particular degree of change. The posted endpoint is also limited to the ADHD-RS-IV; it does not by itself represent every aspect of ADHD or functioning.

The scale’s description and scoring range are reported, but the registry record does not report a threshold for a clinically important change. The endpoint should therefore be read as a measured difference in rating-scale change, not as a direct measure of whether a particular individual experienced a meaningful benefit.

7. Results Posted in the Registry

• 100mg SPN-812: mean -16.70 versus -10.50 on control; difference -6.20 (95% CI -12.56 to 0.16), standardized effect d = -0.45; z-test p = 0.056.
• 200mg SPN-812: mean -18.40 versus -10.50 on control; difference -7.90 (95% CI -14.44 to -1.36), standardized effect d = -0.55; z-test p = 0.018.
• 300mg SPN-812: mean -18.60 versus -10.50 on control; difference -8.10 (95% CI -14.37 to -1.83), standardized effect d = -0.60; z-test p = 0.011.
• 400mg SPN-812: mean -19.00 versus -10.50 on control; difference -8.50 (95% CI -14.88 to -2.12), standardized effect d = -0.62; z-test p = 0.009.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • 100mg SPN-812: mean 2.60 versus 3.00 on control; difference -0.40 (95% CI -0.88 to 0.08), standardized effect d = -0.39; z-test p = 0.100.
  • 200mg SPN-812: mean 2.60 versus 3.00 on control; difference -0.40 (95% CI -0.91 to 0.11), standardized effect d = -0.35; z-test p = 0.122.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 100mg SPN-812 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 200mg SPN-812 and the control. The interval gives the range of effects that remain compatible with the data.

Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • 100mg SPN-812: mean -1.40 versus -0.80 on control; difference -0.60 (95% CI -1.18 to -0.02), standardized effect d = -0.46; z-test p = 0.041.
  • 200mg SPN-812: mean -1.50 versus -0.80 on control; difference -0.70 (95% CI -1.27 to -0.13), standardized effect d = -0.54; z-test p = 0.016.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for 100mg SPN-812 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for 200mg SPN-812 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry record posts two secondary outcomes: CGI-I at Week 8 and change in CGI-S from baseline to Week 8. These are global clinician-rating measures that address aspects of clinical impression distinct from the symptom-specific ADHD-RS-IV primary outcome. They can add context, but they do not replace the primary endpoint or independently establish the overall interpretation of the trial.

Across the secondary outcome summaries, values differ among placebo and active-dose groups. However, the registry record does not describe the scoring direction or provide enough scale interpretation to make all of those numerical patterns self-explanatory. The CGI-I outcome is reported at Week 8, while CGI-S is reported as a baseline-to-Week 8 change. Those distinct measures and time descriptions should not be treated as interchangeable with the ADHD-RS-IV change score.

Sponsor analyses are posted for only some of the secondary comparisons. The record does not report sponsor analyses for every active dose on these outcomes, nor does it explain why the posted analyses are limited in that way. Recalculated comparisons should not be taken as an alternative sponsor analysis, particularly given the discrepancy flagged for the primary endpoint.

Secondary outcomes commonly carry less inferential weight when multiple outcomes and comparisons are examined without a reported adjustment or prespecified hierarchy. The registry record does not say whether multiplicity was addressed. As a result, the secondary findings are most appropriately read as additional descriptive evidence rather than as a separate, definitive test of the primary question. Their relationship to the primary outcome is contextual: they measure other rated aspects, and their interpretation depends on scale definitions, analysis details, and the trial’s unreported testing plan.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale
• Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean change represent?

General explanation: A mean is the arithmetic average of the values in a group. For a change-from-baseline outcome, each participant’s change is calculated from their measurements at the specified time points, and the group mean summarizes those participant-level changes. A negative mean does not mean that every participant’s score fell; individual changes can vary around the group average. In this study, the registry record explicitly identifies lower ADHD-RS-IV change scores as a better outcome.

The standard deviation describes the spread of participant values around the mean. It is not the same as the standard error, which describes the precision of an estimated mean. The primary outcome’s posted standard deviations range from 11.82 in the placebo group to 15.61 in the 200mg group. The spread is substantial relative to the differences between group means, which is one reason the estimated comparisons have uncertainty.

What is a mean difference?

General explanation: A mean difference compares the average outcome in one group with the average in another. The recalculated contrasts use placebo as the reference group. Negative values indicate a lower mean change in the active-dose group than in placebo for this endpoint, consistent with the endpoint’s stated direction. A contrast is an estimate, not a statement that every participant in one group had a lower change than every participant in the other group.

The recalculations use posted group means, standard deviations, and participant counts to form simple, unadjusted comparisons. They are useful as a transparent descriptive cross-check, but they are not a reconstruction of every element of the sponsor’s statistical analysis. The registry record flags a discrepancy. For that reason, the sponsor’s results should take precedence when describing the trial’s own inferential analysis.

How should a confidence interval be read?

General explanation: A confidence interval expresses uncertainty around an estimated quantity. A narrower interval indicates greater precision than a wider interval, all else being equal. For a mean difference, an interval that includes zero is compatible with no difference under that interval procedure; an interval entirely on one side of zero is not. This does not establish the probability that a particular hypothesis is true, and it does not give the range of individual responses.

The sponsor’s primary-outcome intervals are reported at the 95% level. The 100mg interval runs from -13.4 to 1.0 and includes zero. The reported intervals for 200mg, 300mg, and 400mg lie below zero. These are results from the sponsor’s posted ANOVA comparisons and should not be conflated with the separately recalculated intervals.

What does a p-value add?

General explanation: A p-value measures how unusual data at least as incompatible with a specified null model would be if that model and the analysis assumptions held. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. A smaller p-value does not automatically mean a more important difference.

The recalculated p-values are unadjusted and come from simple comparisons. They should not be treated as sponsor-reported p-values. The registry record reports sponsor p-values, but a discrepancy is flagged between the sponsor analysis and recalculation. The posted record does not explain the discrepancy, so its cause should not be inferred.

Why can analysis choices matter?

General explanation: An analysis can use different assumptions about variability, baseline values, and the way repeated or missing measurements are handled. Those choices can affect estimates and uncertainty. The registry record identifies ANOVA for the sponsor’s primary-outcome comparisons, but does not provide enough detail to reconstruct the full analysis model or its assumptions. The primary endpoint description identifies an Intent-to-Treat population, although its definition requires at least one post-baseline assessment. How participants without such an assessment were treated is not reported in the registry record.

For secondary outcomes, the sponsor reports ANOVA for the posted CGI-I comparisons and ANCOVA for the posted CGI-S comparisons. General statistical practice distinguishes these methods by the model terms used, but the registry record does not provide model specifications or covariates. The labels alone are not enough to infer which covariates were included or how the analyses were implemented.

Finally, multiple outcomes and comparisons create a multiplicity issue: when many hypotheses are tested, the chance of at least one apparently notable result can rise if no adjustment or hierarchy is used. Whether the trial used a prespecified testing sequence or adjustment is not reported in the registry record. The posted estimates remain useful descriptions, but inferential claims across all comparisons should be interpreted with that limitation in mind.

11. Confidence Intervals and Precision

Precision concerns how narrowly the data estimate a group contrast, rather than whether the contrast is important or applies to every participant. For the primary endpoint, the sponsor-reported 95% confidence intervals vary in width and position. The interval for 100mg extends from -13.4 to 1.0 and includes zero. The intervals reported for 200mg, 300mg, and 400mg extend from -15.1 to -0.7, -15.3 to -0.9, and -15.8 to -1.3. Those intervals are all on the negative side of zero, but they still span a range of possible mean differences.

The interval endpoints matter alongside the point estimate. For example, an estimate can be negative while its interval includes zero, indicating that the data are not very precise about whether the average contrast is negative or could be near zero under the reported method. An interval that excludes zero narrows that particular uncertainty but does not remove uncertainty about the size of the difference or the experience of individual participants.

The recalculated intervals differ from the sponsor’s reported intervals, and the registry record flags a discrepancy. The recalculated comparisons are unadjusted summaries, whereas the sponsor reports ANOVA comparisons. The sponsor’s analysis takes precedence for interpretation of the trial’s own inferential results. The record does not explain the discrepancy, so it is not possible to attribute it to a specific analytic choice from the posted information.

Group standard deviations also show that participant changes varied within each arm. That within-group variation, together with the available group sizes, contributes to uncertainty in the estimated contrasts. The registry record does not report confidence intervals for all secondary outcomes or identify intervals for individual participant outcomes. Precision should therefore be judged from the posted estimates and intervals, without assuming that a point estimate is exact or that an average describes each child.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations for a two-group comparison, not a reconstruction of the trial’s original enrollment plan. For this continuous-outcome setting, the figures are participants per arm, not total events. The assumptions listed for the illustration are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to a stated fraction of the observed effect. The trial’s own original design assumptions and sample-size justification are not reported in the registry record.

The rows describe planning for 100%, 75%, or 50% of the observed effect. The columns for 80% and 90% power show how many participants per arm the illustration estimates would be needed to have those respective chances of detecting the stated effect under the listed assumptions, if the assumptions hold. For example, planning for the full observed 100mg primary contrast gives 77 participants per arm for 80% power and 103 participants per arm for 90% power. The corresponding figures for the full observed 200mg contrast are 53 and 71; for 300mg, 45 and 60; and for 400mg, 41 and 55.

Smaller effects are harder to distinguish from random variation, so planning to detect a smaller fraction of an observed effect requires more participants. The figures for 75% and 50% of the observed effect illustrate that pattern. A curve can be read in the same planning context: it relates assumed effect size to estimated sample size under the stated assumptions. Neither the figures nor the curve say how likely the completed trial was to produce a statistically significant result. This is not observed power.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -6.200; pooled standard deviation σ = 13.688.
2. n = 2 × (1.96 + 0.842)² × 13.688² / -6.200² = 76.5, rounded up to 77 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -6.2                      # observed difference in means
sigma <- 13.6883874959327                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2633527)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 77 (80% power), 103 (90% power)
 75% of observed effect: n per arm = 137 (80% power), 183 (90% power)
 50% of observed effect: n per arm = 307 (80% power), 410 (90% power)
power.t.test: 77.5 
Simulated power at n = 77 per arm: 0.795 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry record contains sponsor-reported primary comparisons from ANOVA and simple unadjusted recalculations based on posted group summaries. The sponsor’s reported mean differences match the recalculated estimates at the displayed precision, but the confidence intervals and p-values differ. For the primary endpoint, the sponsor reports 95% confidence intervals and p-values from its analysis; the recalculated comparisons use unadjusted summary-statistic methods.

The record flags this discrepancy but does not explain its source. It is not possible to determine from the registry record whether it reflects model details, variance assumptions, analysis populations, rounding, or another factor. Those possibilities should not be presented as established explanations. Because the sponsor’s analysis is the trial’s own reported analysis, it takes precedence over the recalculations when describing the study’s inferential findings.

The sponsor’s primary analysis reports the 100mg comparison with an interval that includes zero, while the reported intervals for the other three active doses exclude zero. The simple recalculations are best treated as a check on the posted summary statistics and a way to make the group contrasts more transparent, not as a replacement for the sponsor’s result. Neither analysis resolves limitations that are not addressed in the registry record, including multiplicity and missing-data handling.

15. Multiplicity, Missing Data and Analysis Populations

The study has several opportunities for statistical comparison: four active doses can each be compared with placebo, and the registry record lists a primary endpoint and two secondary outcomes. When multiple hypotheses are tested, the chance of obtaining at least one apparently notable result may increase if the testing strategy does not account for the number or order of comparisons. This is a general statistical concern, not a claim about what happened in this study.

The registry record does not report whether the sponsor used a multiplicity adjustment, a testing hierarchy, or another prespecified strategy to control interpretation across doses and outcomes. It also does not report an interim analysis plan. The recalculated p-values are unadjusted, so they should not be interpreted as accounting for the full set of comparisons. Sponsor results should be read as reported, while recognizing that the registry record does not explain the role of multiplicity in their interpretation.

The primary endpoint defines an Intent-to-Treat population that includes randomized participants who took at least one dose and had baseline and post-baseline ADHD-RS-IV assessments. This definition is reported, but the registry record does not explain how participants without a post-baseline assessment were handled, how missing observations were imputed, or whether any sensitivity analyses were performed. The record also does not give a detailed account of missingness by group or reasons for missing measurements.

These gaps matter because a change-from-baseline analysis requires measurements at relevant time points, and exclusions or assumptions about unobserved measurements can affect the estimate. The available record does not support assumptions about the direction or size of any such effect. Analysis-population details for the secondary outcomes are not reported in the registry record. The trial’s full statistical analysis plan, the rationale for its analysis choices, and any procedures used to address missing data are also not reported.

16. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry record reports zero serious adverse events in each of the five groups: placebo and all four SPN-812 dose groups. It also reports zero deaths in every group. These are counts within the safety populations at risk listed in the record. They describe the serious-event findings recorded during the study; they do not establish that serious events are impossible or characterize risk outside this study.

The number of participants at risk differs among groups in the safety results, and the registry record does not provide further explanation for those group counts. No serious adverse-event terms are listed. The record separately includes counts of participants affected by other adverse events, but those are not serious-event counts and should not be conflated with the serious-event figures.

Safety findings should be interpreted in the context of the study population and its recorded follow-up period through Week 8. The registry record does not provide enough detail to evaluate event timing, severity beyond the serious-event classification, or longer-term safety. Counts alone do not establish a comparative safety profile.

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

The posted primary results describe average ADHD-RS-IV change from baseline to Week 8 in a randomized, placebo-controlled study of children with ADHD. The active-dose group means were numerically lower than the placebo mean, and the endpoint definition identifies lower change as a better outcome. The sponsor’s reported comparisons show that the estimated mean differences and their precision vary across doses; the 100mg interval includes zero, while the other reported intervals do not.

Those findings are not equivalent to a conclusion that every participant improved, or that every participant receiving an active dose had a better outcome than a participant receiving placebo. Group averages and confidence intervals summarize evidence about group-level quantities, not individual outcomes. The study also does not, by itself, establish which dose is preferable, a dose-response relationship, or a clinically meaningful threshold. A threshold for clinically important change is not reported in the registry record.

The result is limited to the specified population, outcome, and follow-up period. It does not establish what happens after Week 8, in other age groups, or on outcomes that were not measured or posted. The secondary global-rating measures provide additional context but have their own scoring and analysis limitations. The record does not report whether multiplicity was addressed, how missing data were handled, or the trial’s original sample-size rationale.

The discrepancy between simple recalculations and sponsor-reported inferential results is another reason to distinguish descriptive contrasts from the trial’s own analysis. The sponsor’s analysis takes precedence, but the registry record does not explain the discrepancy. Taken together, the findings are a report of estimates and uncertainty from this particular study, not a guarantee of an outcome for any individual and not a substitute for evidence beyond the recorded trial.

18. Why This Trial Matters Statistically

This trial illustrates several practical issues in interpreting a multi-arm clinical study. A placebo group provides a reference for each dose, while the continuous primary endpoint allows the size and uncertainty of group contrasts to be described. The posted means, standard deviations, and confidence intervals make it possible to distinguish an estimated difference from the precision with which that difference is known.

The study also illustrates why a sequence of dose-group averages should not automatically be called a dose-response relationship. The means show a numerical pattern across the listed doses, but the registry record does not report a formal dose-response test. A pattern in group estimates is not the same as a tested trend, particularly when within-group variability is substantial and multiple comparisons are possible.

The record’s discrepancy between sponsor analyses and simple recalculations highlights the importance of identifying which analysis produced a result. Recalculations from summary statistics can help check or explain estimates, but they may not reproduce a trial’s model or analysis plan. The sponsor’s own analysis takes precedence for the trial’s inferential findings, and the unexplained difference remains a limitation of the posted information.

Finally, the study underscores that a registry record may identify an analysis population and outcome definitions without reporting the full statistical plan. Multiplicity, missing-data methods, and sample-size justification affect how results should be interpreted. Recognizing what is documented and what is not is part of sound statistical reading, especially when a trial reports several doses and outcomes.

19. 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 study is a Phase 2 trial with a recorded follow-up endpoint at Week 8. The registry record does not provide longer-term outcome results, so the posted findings cannot describe durability beyond the study period. The enrolled population is children 6-12 years of age with ADHD; the record does not establish whether the findings generalize to other populations.

Although the study includes four active-dose groups, the registry record does not report a formal dose-response analysis or a prespecified comparison hierarchy. It also does not report whether multiplicity was addressed. This makes it difficult to interpret all dose and outcome comparisons as one coordinated inferential program. The original sample-size assumptions and justification are not reported, so the planning illustrations should not be mistaken for the study’s design rationale.

The record flags a discrepancy between the sponsor’s analyses and simple recalculations but does not explain it. That limits independent reconciliation of the posted estimates and p-values. The sponsor’s analysis remains the relevant trial-reported analysis, while the recalculations are unadjusted checks from summary statistics.

The endpoint population definition requires a baseline and at least one post-baseline assessment, but missing-data procedures and sensitivity analyses are not reported. The record does not provide detailed model specifications, covariates, or analysis assumptions. The scale description defines score direction, but a threshold for clinically important change is not reported. Finally, the registry record’s safety counts do not provide detailed event timing or longer-term follow-up. These limitations constrain interpretation without establishing the direction of any resulting bias.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Efficacy and Safety of SPN-812 (Viloxazine Extended-release Capsule) in Children With ADHD — NCT02633527.
• Registry record last updated 2021-10-27; status last verified 2020-08.
• Results first posted 2021-10-27.
• 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.

23. Record Summary

NCT02633527 is a completed, randomized, quadruple-masked, parallel-group, placebo-controlled Phase 2 study of SPN-812 in children 6-12 years of age with ADHD. The registry record lists 222 participants enrolled and five groups: placebo and once-daily oral capsules of 100mg, 200mg, 300mg, or 400mg SPN-812.

The primary outcome was change in ADHD-RS-IV Total score from baseline to Week 8. Lower change scores were defined as a better outcome. The record also posts CGI-I and CGI-S secondary outcomes. Sponsor primary analyses used ANOVA; the sponsor’s reported results take precedence over simple recalculations because a discrepancy is flagged.

The record reports zero serious adverse events and zero deaths in every group. Multiplicity procedures, missing-data methods, detailed model specifications, and the original sample-size rationale are not reported in the registry record.