The Efficacy and Safety of PRC-063 in Adult ADHD Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Efficacy and Safety of PRC-063 in Adult ADHD Patients (NCT02139124), a randomized phase 3 study. The primary outcome is Change From Baseline in Clinician-administered ADHD-5-Rating Scale Total Score.

2. Clinical Question

3. Trial Design

This completed Phase III study was randomized, placebo-controlled, double-blind, parallel-arm, and multi-center. The registry records quadruple masking. It lists an enrollment of 375 and describes five intervention groups: placebo and PRC-063 at 25 mg, 45 mg, 70 mg, or 100 mg. The trial started in 2014-04, with primary completion in 2014-10. The sponsor was Rhodes Pharmaceuticals, L.P.

The posted primary outcome concerns change from baseline in the clinician-administered ADHD-5-Rating Scale total score. Participants were monitored for 4 weeks on treatment, including a final 2 weeks on a stable dose. Clinicians rated behavior weekly, and the primary outcome used the final week of treatment. The Full Analysis population consisted of randomized subjects who received any amount of study medication and had any ADHD-5-Rating Scale assessments.

The registry reports four sponsor analyses, each comparing a PRC-063 dose with the 0 mg/Day group using ANCOVA. It also posts arm-level means and standard deviations, from which simple unadjusted comparisons have been recalculated. Those recalculations use the 25 mg group as the reference, rather than placebo, so they do not reproduce the sponsor's comparisons. The registry record does not report the original sample-size justification or the assumptions used to plan the trial.

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: The Full Analysis population consists of all randomized subjects who receive any amount of study medication and who have any ADHD-5-Rating Scale assessments.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Clinician-administered ADHD-5-Rating Scale Total Score, measured over 4 weeks.

The primary endpoint was change from baseline in the clinician-administered ADHD-5-Rating Scale total score, measured in units on a scale. The scale has 18 items based on DSM-5 criteria. For each item, a clinician rates how often a behavior is displayed from 0, meaning Never or Rarely, to 3, meaning Very Often. Total scores can range from 0 to 54; lower scores indicate a lower frequency of ADHD symptoms.

Clinicians rated participants each week during 4 weeks of treatment, with the final 2 weeks on a stable dose. The primary outcome was based on the final treatment week. A clinician-rated symptom scale provides a structured way to quantify behavior over the assessment period, rather than relying only on an unstructured overall impression. A change-from-baseline endpoint is intended to describe how scores differ from each participant's starting point. The posted sponsor comparisons, however, are labeled mean differences in final values and come from ANCOVA. The registry record does not explain the model covariates or how the reported final-value comparisons correspond to the change-from-baseline endpoint title.

7. Results Posted in the Registry

• PRC-063 45 mg: mean 19.90 versus 24.20 on control; difference -4.30 (95% CI -8.20 to -0.40), standardized effect d = -0.35; z-test p = 0.031.
• PRC-063 70 mg: mean 24.00 versus 24.20 on control; difference -0.20 (95% CI -3.90 to 3.50), standardized effect d = -0.02; z-test p = 0.916.
• PRC-063 100 mg: mean 18.70 versus 24.20 on control; difference -5.50 (95% CI -9.23 to -1.77), standardized effect d = -0.47; z-test p = 0.004.
• 0 mg/Day: mean 26.10 versus 24.20 on control; difference 1.90 (95% CI -1.86 to 5.66), standardized effect d = 0.16; z-test p = 0.322.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports ANCOVA for the sponsor's four dose-versus-placebo comparisons. ANCOVA, or analysis of covariance, estimates a group contrast while adjusting for one or more covariates. It can account for baseline measurements or other prespecified variables when those variables are included in the model. The registry record does not report which covariates were included, the model specification, or the handling of missing outcome measurements. Therefore, the adjusted estimates cannot be independently reconstructed from the arm-level means and standard deviations alone.

What does a mean difference represent?

A mean difference expresses the contrast between average outcomes in two groups, in the outcome's original scale units. The sign depends on the order of groups used to form the contrast. Here, the sponsor reports final-value differences for each dose versus placebo. The negative estimates for 25 mg, 45 mg, 70 mg, and 100 mg indicate lower final values in the dose group under the sponsor's comparison convention. Because lower ADHD-5-Rating Scale scores correspond to less frequent symptoms, direction can be interpreted in relation to that scale. The outcome title refers to change from baseline, however, and the registry does not explain the apparent distinction between that title and the sponsor analysis parameter.

Why are the recalculations different?

The posted recalculations are unadjusted comparisons derived from arm-level summary statistics. They use PRC-063 25 mg as the reference group, whereas the sponsor's reported ANCOVA comparisons use 0 mg/Day placebo as the reference. They also do not include covariate adjustment. A simple difference between group means need not match an adjusted model estimate, and estimates based on different comparison groups answer different questions. The calculations are useful as a transparent check on summary-statistic contrasts, but they are not a replacement for the sponsor's analysis. Because the record flags a discrepancy, the sponsor's own analysis takes precedence.

How should a confidence interval be read?

A confidence interval gives a range of values compatible with the data and the analysis under its assumptions. It communicates uncertainty around an estimate, not the probability that a specific hypothesis is true. For a mean difference, an interval containing zero is compatible with no difference as well as with differences in either direction. An interval that excludes zero indicates that the observed data are less compatible with a zero contrast under the model's assumptions, but it does not by itself show that the difference is important to patients. The sponsor's confidence intervals are reported at 95%.

What do the p-values add?

A p-value describes how unusual the observed data, or data more extreme, would be under a specified null model. It is not the probability that the null hypothesis is true, and it does not measure effect size. The recalculated unadjusted p-values relate to comparisons against the 25 mg group. The sponsor p-values relate to adjusted dose-versus-placebo comparisons. They therefore should not be treated as competing estimates of the same contrast. The registry record does not report a multiplicity adjustment, so the extent to which the sponsor's inference accounts for testing several doses is not reported in the registry record.

Why does dispersion matter?

The arm-level standard deviations describe how spread out individual outcome values are around each group's mean. Greater variation makes a group mean less precise when other features are comparable. The recalculated comparisons use the posted standard deviations and group sizes to represent uncertainty for an unadjusted mean difference. A pooled standard deviation is a summary of within-group spread used in a standardized effect calculation. Such a standardized effect expresses a mean difference relative to variability; it is not itself measured in ADHD-5-Rating Scale units. The posted recalculations are summary-statistic calculations, not the original trial model.

What can be concluded from the methods record?

The record identifies ANCOVA and the Full Analysis population, but does not report the original statistical analysis plan, model covariates, missing-data method, or the trial's original sample-size assumptions. It also does not report an interim-analysis plan or a multiplicity procedure. These omissions matter because adjustment, missing observations, and multiple comparisons can influence uncertainty and interpretation. No assumption about those procedures should be inferred from the reported estimates alone.

10. Confidence Intervals and Precision

The sponsor's 95% confidence intervals show meaningful uncertainty around each estimated dose-versus-placebo contrast. For PRC-063 25 mg, the estimate was -2.0 and the interval extended from -6.6 to 2.6. For 45 mg, the estimate was -6.9 and the interval extended from -11.5 to -2.2. For 70 mg, the estimate was -2.1 and the interval extended from -6.8 to 2.7. For 100 mg, the estimate was -8.1 and the interval extended from -12.9 to -3.2.

The intervals for 25 mg and 70 mg include zero, so the estimates are compatible with a range that includes no difference as well as differences in either direction. The intervals for 45 mg and 100 mg exclude zero and are entirely on the negative side under the reported contrast convention. Their width still allows a range of plausible effect magnitudes. A confidence interval is not a guarantee that the true value lies within its endpoints, nor does it indicate the probability that a treatment effect is clinically important.

These intervals come from the sponsor's adjusted ANCOVA analyses. The simpler recalculations use another reference group and do not reproduce those intervals. The registry does not give enough model detail to assess how covariate adjustment or missing data affected precision. The interpretation should therefore retain the distinction between adjusted sponsor estimates and unadjusted summary-statistic calculations.

11. 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 planning illustrations express required sample size as participants per arm for 80% power and participants per arm for 90% power. The figures are not total participants across arms and are not total event counts. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each scenario uses the stated fraction of the observed effect as the effect to detect. The trial's original design assumptions are not reported in the registry record, so these planning illustrations should not be read as the assumptions used to design this trial.

In plain terms, the 80% power column gives the number of participants per arm that the illustration estimates would be needed to have an 80% chance of detecting the specified effect under the stated assumptions. The 90% power column applies a higher chance of detection, and therefore requires a larger planned sample for the same effect and assumptions. These are planning quantities, not observed outcomes. They do not tell whether this completed study had adequate power for its actual analyses, and they are not observed power.

Rows that plan for 75% or 50% of the observed effect ask what sample size would be needed to detect a smaller effect than the observed one. Smaller effects are harder to distinguish from random variation, so they require more participants under the same assumptions. Estimates based on a very small observed contrast can produce especially large planning figures. The illustrations are sensitive to the effect chosen and should be understood as conditional scenarios, not as a revised design for the completed trial. The posted curve and planning values are different ways of conveying this dependence of sample size on the assumed effect.

12. 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 = -4.300; pooled standard deviation σ = 12.161.
2. n = 2 × (1.96 + 0.842)² × 12.161² / -4.300² = 125.5, rounded up to 126 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 <- -4.3                      # observed difference in means
sigma <- 12.1606349851989                     # 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(2139124)
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 = 126 (80% power), 169 (90% power)
 75% of observed effect: n per arm = 224 (80% power), 299 (90% power)
 50% of observed effect: n per arm = 503 (80% power), 673 (90% power)
power.t.test: 126.5 
Simulated power at n = 126 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.

13. Analyses Reported by the Sponsor

The sponsor's analyses compare each PRC-063 dose with the 0 mg/Day placebo group using ANCOVA. The registry reports a 95% confidence interval and p-value for each comparison. The 25 mg and 70 mg intervals include zero, while the 45 mg and 100 mg intervals exclude zero. These are the trial sponsor's adjusted results and take precedence over the simple recalculations.

The recalculations use the arm-level means and standard deviations, but use PRC-063 25 mg as the reference group. They are unadjusted comparisons and therefore differ from the sponsor's dose-versus-placebo analysis both in reference group and method. The recalculated 45 mg and 100 mg contrasts versus 25 mg are not the same estimands as the sponsor's 45 mg and 100 mg contrasts versus placebo. Their estimates or p-values should not be used to challenge or replace the sponsor's analyses.

The registry marks a discrepancy between the posted summaries and recalculation. The record does not explain its cause, and it would be inappropriate to assign one. Differences in reference group and adjustment are evident from the posted information, but the full original model specification is not reported in the registry record. The sponsor results are the primary basis for describing the trial's reported comparisons.

14. Multiplicity, Missing Data and Analysis Populations

The registry reports four sponsor comparisons, one for each PRC-063 dose against placebo. Testing several comparisons creates a multiplicity question: when many hypotheses are examined, the chance of at least one apparently unusual result can increase if each is interpreted without adjustment. The registry record does not report whether a multiplicity procedure was used, whether the comparisons followed a prespecified hierarchy, or how the family of tests was defined. The reported p-values therefore should be understood as the values posted, without assuming that they were adjusted for multiple comparisons.

The record identifies ANCOVA as the sponsor's method, but does not describe the covariates, model diagnostics, or exact model specification. It also does not report the original analysis plan or an interim-analysis plan. No claim about whether interim testing occurred or whether it affected statistical error rates can be made from the record.

The primary outcome population is defined as randomized subjects who received any amount of study medication and had any ADHD-5-Rating Scale assessments. This definition is reported as the Full Analysis population. The registry record does not say how many participants contributed to each sponsor comparison, how incomplete repeated assessments were handled, or what missing-data assumptions were used. It does not report a sensitivity analysis for missing outcomes. The distinction matters because estimates may depend on which participants have usable measurements and how missing values are addressed.

The registry lists one outcome measure and four analyses, and reports no posted secondary outcomes. This does not establish that no other analyses were conducted; it describes what is reported in the registry record. Without an analysis plan and details on missingness and multiplicity, the sponsor's estimates can be described, but the full inferential framework cannot be independently assessed.

15. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: headache (2.6%), feeling jittery (1.4%), osteoarthritis (1.4%), uterine cancer (1.4%), calculus urinary (1.4%).

The registry reports serious adverse event counts and counts for other adverse events by group. Serious adverse events were reported for 2 participants in the placebo group, 4 in PRC-063 25 mg, 2 in PRC-063 45 mg, 2 in PRC-063 70 mg, and 4 in PRC-063 100 mg. The corresponding at-risk group sizes were 78, 77, 73, 73, and 74. These counts describe the registry entries; they do not establish that an event was caused by treatment or permit a firm comparison of risk.

The listed serious-event terms include headache at 2.6%, Feeling jittery at 1.4%, osteoarthritis at 1.4%, uterine cancer at 1.4%, calculus urinary at 1.4%, and diarrhoea at 1.4%. The record does not provide enough context to attribute these terms to a particular dose group in this summary. Deaths are not reported in the registry record. Adverse-event counts are descriptive, and the registry information alone does not determine clinical significance or causality.

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

The registry reports that the sponsor's adjusted comparisons for PRC-063 45 mg and 100 mg had negative estimates with 95% confidence intervals that excluded zero. The estimates for 25 mg and 70 mg also were negative, but their intervals included zero. These patterns describe the posted comparisons of final values against placebo; they do not by themselves establish how meaningful any difference would be to participants.

The endpoint is a clinician-rated symptom-frequency scale, and lower scores indicate less frequent symptoms. The sponsor analysis parameter is labeled mean difference in final values, while the primary endpoint title describes change from baseline. The registry does not explain this difference in labeling. The simple recalculations use the 25 mg arm as reference and are unadjusted, so they answer a different question and do not override the sponsor analysis.

The results do not establish that every participant responded in the same way, nor do group averages describe individual outcomes. The confidence intervals show uncertainty, and the missing methodological details limit independent assessment. The registry reports safety counts as well, but these counts do not establish causation or a complete safety profile. The findings should be read as the results of this trial and its reported analyses, not as medical advice or a universal prediction.

17. Why This Trial Matters Statistically

This trial is statistically instructive because it reports multiple active-dose comparisons, arm-level summaries, and sponsor-adjusted analyses in the same registry record. That makes the choice of comparator and analysis method central to interpretation. A simple contrast against the 25 mg group cannot be read as if it were the sponsor's dose-versus-placebo ANCOVA contrast. Naming the estimand and reference group is essential before comparing estimates or p-values.

The posted confidence intervals also show why an estimate alone is insufficient. The 45 mg and 100 mg sponsor intervals exclude zero, whereas those for 25 mg and 70 mg include zero. Interval width conveys uncertainty, while the estimate conveys the direction and scale of the contrast. Neither statistical compatibility with zero nor exclusion of zero answers whether a difference is important in practice.

The record also illustrates limits in registry reporting. It identifies the analysis method and analysis population, but does not report the covariates, missing-data approach, multiplicity procedure, or original planning assumptions. Those omissions do not invalidate the posted results, but they constrain independent evaluation and explain why recalculation cannot reproduce the sponsor's adjusted estimates. Transparent reporting of the planned analysis and its assumptions helps readers distinguish a trial's intended inference from exploratory or unadjusted calculations.

18. 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 registry record does not report the original sample-size justification or the assumptions used to plan the trial. The planning illustrations are based on the observed contrasts and should not be mistaken for the trial's design rationale. The original statistical analysis plan, interim-analysis plan, and multiplicity procedure are also not reported.

Although ANCOVA is named for the sponsor analyses, the covariates, model details, and missing-data method are not reported. The primary endpoint is described as change from baseline, while the sponsor comparisons are labeled as differences in final values. The registry does not explain this distinction. The arm-level summary-statistic recalculations use PRC-063 25 mg as the reference and are unadjusted; they cannot independently reproduce the sponsor's placebo comparisons. The record flags a discrepancy, and the sponsor's analysis takes precedence.

The posted primary analysis population includes randomized subjects who received study medication and had any ADHD-5-Rating Scale assessments. The registry does not report the extent of missing outcome data or sensitivity analyses. It reports no secondary outcomes in the posted results, which limits the outcome scope available for interpretation. Safety entries are counts and listed terms; the record does not establish causality. These reporting limitations constrain conclusions about robustness, multiplicity, and generalizability beyond the reported trial population.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: The Efficacy and Safety of PRC-063 in Adult ADHD Patients — NCT02139124.
• Registry record last updated 2019-05-07; status last verified 2019-04.
• Results first posted 2019-05-07.
• 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.

22. Record Summary

The registry describes a completed, randomized, double-blind, placebo-controlled, parallel-arm Phase III study of PRC-063 in adults with ADHD. It lists four dose groups and a placebo group, with an enrollment of 375. Participants were monitored for 4 weeks on treatment, and the primary outcome was based on the final week.

The primary measure was clinician-rated change from baseline in ADHD-5-Rating Scale total score. The sponsor reported ANCOVA comparisons of each dose with placebo. The intervals for 45 mg and 100 mg excluded zero; those for 25 mg and 70 mg included zero. Simple recalculations from arm summaries use a different reference group and are unadjusted, so the sponsor analyses take precedence. Key details on multiplicity, missing-data handling, model covariates, and original sample-size planning are not reported in the registry record.