Study in Healthy Volunteers to Prove That Two Different Formulations of Rotigotine Patches Deliver Equivalent Drug Amount to the Body: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study in Healthy Volunteers to Prove That Two Different Formulations of Rotigotine Patches Deliver Equivalent Drug Amount to the Body (NCT01059903), a randomized phase 1 study. The primary outcome is AUC(0-tz) of Unconjugated Rotigotine.

2. Clinical Question

In a crossover study, participants receive treatments in sequence, so comparisons can draw on measurements made under both formulations. General statistical context: this structure can help account for stable differences between people, but analysis must also consider treatment order and time-related effects. The registry describes the crossover and sequence order; details of how the sponsor handled those features are not reported in the registry record.

3. Trial Design

This was a phase 1, randomized, open-label, single-site crossover trial in healthy volunteers. Its official title describes evaluation of bioequivalence after a single dose of rotigotine transdermal patch, comparing two formulations. The registry marks the study as completed. The start is listed as 2010-01 and primary completion as 2010-02.

The two sequences differed in which formulation was applied first. In one, PR2.2.1 was followed by PR2.1.1; in the other, PR2.1.1 was followed by PR2.2.1. Each application used a 4.5 mg/10 cm2 patch, with a washout phase of at least 5 days between applications. The registry does not describe further details about the washout rationale, adherence, or the conduct of each study period.

Masking was none, so the trial was open-label. Random allocation and treatment order are recorded, but the allocation method and concealment procedures are not reported in the registry record. Although the study is identified as single-site, the site itself is not named in the registry record for the registry record.

The registry lists enrollment as 50. For the primary pharmacokinetic endpoint, the posted summaries show 40 observations under each formulation, and the endpoint population is named as the Pharmacokinetic Set. The reason these outcome counts do not match the enrollment figure is not reported in the registry record. The trial’s original sample-size assumptions, including any target for precision or equivalence testing, are also not reported.

The crossover approach is relevant to interpretation: a participant’s measurements may be correlated across treatment periods. General statistical context: analyses of crossover data often account for within-participant correlation, sequence, and period. The registry identifies an ANOVA for the sponsor’s reported analysis but does not describe its model terms or provide enough detail to determine how those design features were handled.

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: Eight subjects that fulfilled predefined criteria for patch adhesiveness were excluded from the statistical analysis on the PKS. The predefined criteria were patch adhesiveness smaller than 75% at any timepoint or an adhesiveness lower than 90% for 12 hours or more.

Period 1: First Intervention- 24 Hours

Reasons for not completing this period:

Period 2: Washout Period (>= 5 Days)

Period 3: Second Intervention- 24 Hours

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic Set (PKS)

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 AUC(0-tz) of Unconjugated Rotigotine, measured over 0 h (predose), 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h (before patch removal in the morning of Day 2), 25 h, 26 h, 28 h, 30 h, 32 h, 36 h, 40 h, and 48 h.

The primary endpoint is AUC(0-tz) of unconjugated rotigotine, measured in ng/ mL*h. AUC is the area under a concentration-time curve. In this study, the registry defines AUC(0-tz) as the area from zero up to the last analytically quantifiable concentration. The stated sampling schedule extends from predose through 48 h, with measurements at the listed intervening times; 24 h is described as before patch removal in the morning of Day 2.

As a pharmacokinetic measure, AUC captures exposure across the observed concentration-time interval rather than relying on one concentration measurement. Comparing this measure between formulations is relevant to the stated bioequivalence question: the study aims to compare the amount of drug delivered to the body after sequential application of the two patches. The endpoint concerns unconjugated rotigotine, not a clinical symptom or patient-centered outcome.

The registry reports group means and standard deviations for the primary measure. General statistical context: a mean describes the average observed value in a group, while a standard deviation describes variation among observations around that mean. Neither statistic alone establishes equivalence. A formal equivalence conclusion depends on the analysis and on a prespecified margin defining differences considered acceptably small. That margin and the registry’s full formal decision rule are not reported in the registry record.

7. Results Posted in the Registry

• Rotigotine PR2.1.1: mean 5.47 versus 5.27 on control; difference 0.20 (95% CI -1.04 to 1.44), standardized effect d = 0.07; z-test p = 0.750.

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.

AUC(0-tz) Norm (Apparent Dose) of Unconjugated Rotigotine

• 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:
  • Rotigotine PR2.1.1: mean 2.66 versus 2.57 on control; difference 0.10 (95% CI -0.32 to 0.51), standardized effect d = 0.10; z-test p = 0.654.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Rotigotine PR2.1.1 and the control. The interval gives the range of effects that remain compatible with the data.

AUC(0-tz) Norm (Body Weight) of Unconjugated Rotigotine

• 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:
  • Rotigotine PR2.1.1: mean 434.10 versus 412.94 on control; difference 21.16 (95% CI -76.89 to 119.21), standardized effect d = 0.09; z-test p = 0.672.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Rotigotine PR2.1.1 and the control. The interval gives the range of effects that remain compatible with the data.

AUC(0- ∞) Norm (Apparent Dose)

• 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:
  • Rotigotine PR2.1.1: mean 2.71 versus 2.62 on control; difference 0.09 (95% CI -0.33 to 0.52), standardized effect d = 0.10; z-test p = 0.664.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Rotigotine PR2.1.1 and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcomes extend the primary exposure comparison through normalized AUC measures, Cmax, Tmax, and mean residence time. The listed measures include normalization by apparent dose or body weight and AUC through infinity. Together, these endpoints describe related dimensions of the pharmacokinetic profile rather than independent clinical outcomes. The displayed secondary summaries generally show values for both formulations, while the available unadjusted comparisons do not establish a clear separation between them.

This broad pattern is consistent with the primary result in the limited sense that the posted summaries do not show a strong, consistent arithmetic-scale difference across the reported measures. It does not prove that all measures are equivalent. A secondary endpoint may use a different scale, have different variability, or answer a distinct pharmacokinetic question. The registry reports a sponsor analysis for the primary endpoint, but no corresponding sponsor analyses for the secondary endpoints listed in the registry record used.

Unadjusted secondary results carry less weight when many outcomes are assessed. General statistical context: examining multiple outcomes increases the chance that some apparent differences arise by chance, especially when no adjustment or prespecified testing hierarchy is used. The registry lists 15 outcome measures and 3 analyses, but a multiplicity adjustment or hierarchy is not reported in the registry record. The secondary results should therefore be viewed as supportive descriptive information, not as a collection of independent confirmatory tests.

The secondary endpoints also do not replace the primary endpoint or resolve the missing details about the formal equivalence margin. Their value is in showing how the comparison looks across related pharmacokinetic measures, while keeping in mind that the registry does not report a sponsor-model result for each one.

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

• AUC(0-tz) Norm (Apparent Dose) of Unconjugated Rotigotine
• AUC(0-tz) Norm (Body Weight) of Unconjugated Rotigotine
• AUC(0- ∞) Norm (Apparent Dose)
• AUC(0- ∞) Norm (Body Weight)
• Cmax, Norm (Apparent Dose) of Unconjugated Rotigotine
• Cmax, Norm (Body Weight) of Unconjugated Rotigotine
• Tmax of Unconjugated Rotigotine
• Mean Residence Time (MRT) of Unconjugated Rotigotine

9. Statistical Interpretation

10. Statistical Methods Explained

Several statistical ideas help distinguish the posted summaries from the sponsor’s analysis and explain what can be inferred from each.

What does the mean difference describe?

The primary group summaries report means for each formulation. The unadjusted recalculation expresses their contrast as a mean difference: 0.202 ng/ mL*h for PR2.1.1 relative to PR2.2.1. This is an arithmetic-scale comparison. It is useful as a straightforward description of the reported group averages, but it does not necessarily match the estimand or model used in the sponsor’s bioequivalence analysis.

General statistical context: a mean difference is on the original measurement scale. Its interpretation depends on the units and endpoint. A difference of 0.202 ng/ mL*h is an exposure-scale contrast, not a percentage change and not a clinical outcome. No percentage conversion is needed to interpret the sponsor’s ratio analysis, and no additional calculation should be inferred from the posted summaries.

What does the confidence interval add?

A confidence interval describes a range of values reasonably compatible with the data under the assumptions of the analysis. The recalculated interval runs from -1.038 to 1.442 ng/ mL*h. It includes zero, which is the value corresponding to no arithmetic mean difference under this contrast. The interval also spans values on either side of zero, so the summary does not precisely establish the direction of the arithmetic-scale difference.

General statistical context: an interval is not a statement that the true value has a particular probability of lying within the observed limits. Its coverage interpretation depends on the method and assumptions used to construct it. A confidence interval also does not automatically define an equivalence test. Equivalence requires comparing an interval with prespecified acceptable bounds; those bounds are not reported in the registry record.

Why distinguish the sponsor model from the recalculation?

The sponsor analysis is reported as an ANOVA of a ratio of geometric LS-means and gives a 90% confidence interval. A ratio on a geometric scale is not the same quantity as an arithmetic mean difference. General statistical context: geometric summaries are commonly used for positive, potentially skewed pharmacokinetic measures, and a ratio expresses a relative comparison rather than a difference in the original units. The registry does not provide the model specification, transformations, covariates, or the equivalence bounds, so the exact model cannot be reconstructed from the record.

The recalculation is labelled unadjusted because it uses the posted summary statistics rather than individual-level crossover data and a fitted model. It cannot recover the within-person covariance or evaluate sequence and period effects. In a crossover design, measurements from the same person may be related; accounting for that relation can affect standard errors and intervals. The posted group summaries do not contain the paired measurements needed to reproduce such an analysis.

What is the role of the p-value?

The unadjusted p-value is 0.75. General statistical context: a p-value measures how compatible the observed data are with a specified null model, assuming that model and its assumptions hold. It is not the probability that the null hypothesis is true, and it is not a measure of the chance that the formulations are equivalent. A conventional test for a difference and a formal equivalence assessment have different null hypotheses and decision rules.

The registry does not report a p-value for the sponsor’s ratio analysis. It does report that analysis as non-inferiority or equivalence in type and supplies a 90% confidence interval. Without the margin and decision rule, the confidence interval cannot be judged against the formal criterion solely from the registry record.

Why does the crossover design matter?

Randomized treatment order helps define which formulation was applied first, and the two sequences reverse the order of the products. A crossover comparison can be efficient because each participant can contribute measurements under both treatments. General statistical context: efficiency depends on appropriate handling of the repeated measurements and on the assumptions that make period comparisons interpretable. A washout is intended to separate treatment periods, but its adequacy cannot be evaluated from the washout duration alone.

The registry records a washout phase of at least 5 days and an ANOVA method, but does not report the sponsor’s model terms or details about carryover assessment. It is therefore not possible to establish from the registry record how sequence, period, or within-participant correlation were treated. This limits independent replication of the sponsor’s analysis.

What do the secondary measures add?

The registry lists pharmacokinetic outcomes that include normalized AUC measures, Cmax, Tmax, and mean residence time, as well as AUC measures extending to infinity. These outcomes describe different aspects or normalizations of exposure and concentration over time. General statistical context: related outcomes can provide a broader pharmacokinetic profile, but multiple comparisons raise the possibility of chance findings when many results are examined. The registry record does not report a multiplicity procedure or a hierarchy for these analyses.

11. Confidence Intervals and Precision

The recalculated primary mean difference is 0.202 ng/ mL*h, and its 95% confidence interval extends from -1.038 to 1.442 ng/ mL*h. Because zero lies within this interval, the recalculation does not rule out no arithmetic mean difference. Its limits also allow differences in either direction, so it does not pin down the exact contrast closely. The posted standard deviations, 3.143 for PR2.2.1 and 2.475 for PR2.1.1, indicate variation in the observed endpoint within each formulation summary.

Precision and equivalence are related but not interchangeable. General statistical context: a narrow interval may make it easier to rule out differences beyond an acceptable range, but whether an interval is narrow enough depends on a margin chosen before interpreting the data. The registry does not report such a margin for the primary endpoint. Therefore, the recalculated 95% interval cannot by itself establish or exclude formal equivalence.

The sponsor’s analysis uses a different scale and a 90% confidence interval for the geometric LS-means ratio. The reported ratio and both limits are below 1. The registry does not provide the equivalence bounds needed to judge that interval against an acceptance criterion, and its model details are not reported in the registry record. The sponsor’s interval is therefore an important reported analysis, but the record does not allow an independent check of the full equivalence decision.

These intervals also reflect different analyses: the arithmetic-scale recalculation from summary statistics and the sponsor’s model-based ratio. They should not be treated as interchangeable descriptions of one exact estimand. The registry does not report a confidence interval for every outcome in the form needed to reproduce the sponsor’s complete analysis.

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 planning figures are illustrations based on the observed effect, not the trial’s original design calculation. For the continuous outcomes, the displayed figures are participants per arm, not a total across the study. The planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original trial’s own sample-size assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding illustrative number per arm for a 90% chance. These are planning calculations, not guarantees: actual performance depends on the true effect, variability, analysis, and assumptions.

The rows use 100%, 75%, and 50% of the observed effect. As the effect to detect becomes smaller, more participants are required to distinguish it from random variation at the stated power and significance level. For example, the primary endpoint’s planning row for 100% of the observed effect gives 3,080 participants per arm for 80% power and 4,123 participants per arm for 90% power; the row for 50% gives 12,319 and 16,491, respectively. These figures are illustrations, not a recommendation or evidence about the design actually used.

This is not observed power. It is a set of hypothetical planning estimates derived from the observed effect and the stated assumptions. The registry record does not report that the trial was designed using these calculations.

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 = 0.202; pooled standard deviation σ = 2.829.
2. n = 2 × (1.96 + 0.842)² × 2.829² / 0.202² = 3,079.6, rounded up to 3,080 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 <- 0.202                      # observed difference in means
sigma <- 2.82928369910124                     # 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(1059903)
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 = 3,080 (80% power), 4,123 (90% power)
 75% of observed effect: n per arm = 5,475 (80% power), 7,330 (90% power)
 50% of observed effect: n per arm = 12,319 (80% power), 16,491 (90% power)
power.t.test: 3080.5 
Simulated power at n = 3,080 per arm: 0.798 (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 sponsor’s reported primary analysis is an ANOVA comparing the ratio of geometric LS-means, with a 90% confidence interval. The ratio and both limits are below 1. The registry classifies this analysis as non-inferiority or equivalence, but does not report the equivalence margin or the full decision rule. Without those details, the interval cannot be independently evaluated against the criterion for declaring bioequivalence.

The recalculation is different: it compares the posted arithmetic means and gives a mean difference of 0.202 ng/ mL*h, a 95% confidence interval from -1.038 to 1.442, and an unadjusted p-value of 0.75. It is a simple comparison of posted summary statistics, not a reproduction of the sponsor’s ANOVA. It does not use individual crossover measurements or account for within-participant correlation and model terms that may have been used in the sponsor analysis.

Because the analyses use different scales, methods, and interval levels, their numerical results should not be read as direct substitutes. The sponsor’s analysis is the registry’s own reported model-based result for the stated bioequivalence question; the recalculation is a secondary descriptive check. The registry record does not include enough model detail to reconstruct the sponsor’s result or confirm its decision rule.

15. Multiplicity, Missing Data and Analysis Populations

The record identifies one primary pharmacokinetic outcome and lists secondary outcomes including normalized AUC measures, AUC to infinity, Cmax, Tmax, and mean residence time. It also records 15 outcome measures and 3 analyses. The registry does not report a multiplicity adjustment, a testing hierarchy, or which secondary outcomes were intended to be confirmatory. General statistical context: when many outcomes are tested, unadjusted p-values do not control the overall chance of a false-positive finding across all tests. That is why secondary results without a stated multiplicity plan are best treated as exploratory or descriptive.

The primary outcome population is the Pharmacokinetic Set. The registry does not report the set’s detailed inclusion rules, the number excluded from it, or reasons for exclusion. The posted primary summaries list 40 observations under each formulation, while enrollment is recorded as 50. The relationship between those figures is not explained in the registry record. Missing endpoint values, handling of incomplete sequences, and imputation procedures are also not reported.

The trial is randomized and crossover, with two treatment orders and a washout of at least 5 days. The sponsor analysis is identified as ANOVA, but its model specification is not reported. In particular, the registry record does not say which sequence or period terms were included, how within-participant dependence was handled, or whether carryover was assessed. These omissions matter because the crossover structure creates repeated measurements that are not necessarily independent.

The record does not report interim analyses, the original sample-size justification, or the sponsor’s prespecified equivalence margin and complete decision rule. These are distinct reporting gaps: the observed summaries can still be described, but the design rationale and the basis for a formal equivalence conclusion cannot be fully checked from the registry record.

16. 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 non-serious adverse event terms

The registry reports serious adverse events affecting 0 of 49 at risk in the PR2.2.1 group and 0 of 49 at risk in the PR2.1.1 group. No serious adverse-event terms are listed. The deaths fields are not populated, so death counts are not reported in the registry record.

For other adverse events, the record reports 23 affected in the PR2.2.1 group and 26 affected in the PR2.1.1 group, with 49 at risk in each group. These figures are recorded separately by formulation. Because this was a crossover study, treatment exposure and the way adverse events were assigned to groups should be interpreted in the context of the sequence design; further attribution details are not reported in the registry record.

Zero reported serious adverse events in the posted groups means none were recorded as affecting participants in those registry summaries. It does not establish that the risk of serious events is zero or rule out uncommon events. The registry record does not provide additional event descriptions or enough detail to assess timing, severity grading, or causal attribution.

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

The trial’s central statistical question concerns pharmacokinetic comparability of two rotigotine patch formulations in healthy volunteers. The primary outcome is AUC(0-tz) for unconjugated rotigotine, and the posted results include group means, variability, an unadjusted arithmetic-scale comparison, and a sponsor-reported geometric LS-means ratio analysis.

The recalculated mean difference is 0.202 ng/ mL*h, with a 95% confidence interval from -1.038 to 1.442 and an unadjusted p-value of 0.75. The interval includes zero and allows differences in either direction. This does not demonstrate exact equality. Nor does a non-significant difference test establish equivalence: formal equivalence requires an acceptable margin and a decision rule, neither of which is reported in the registry record.

The sponsor’s reported ratio analysis is relevant to the stated bioequivalence aim, but the registry does not provide its model details or the margin needed to independently verify the formal conclusion. The simple recalculation and sponsor analysis are not interchangeable: they use different scales and methods, and the recalculation cannot use the paired participant-level information inherent in the crossover design.

The findings concern measured drug exposure over the specified pharmacokinetic sampling period. They do not establish a clinical effect, symptom benefit, or long-term safety outcome. The population was healthy volunteers, so the record does not directly address outcomes in people with a specific disease. The safety summaries report no serious adverse events in the two posted groups, but the information is limited and does not exclude rare harms.

In short, the registry supports describing the observed pharmacokinetic summaries and the sponsor’s reported analysis. It does not supply all the design and analysis details needed to independently assess the formal equivalence decision, and the simple recalculation should not be read as a clinical conclusion.

18. Why This Trial Matters Statistically

This study illustrates why the statistical question and the analysis scale matter. A conventional comparison of arithmetic means asks whether the data indicate a difference on the original measurement scale. Bioequivalence asks a different question: whether the relative exposure comparison is sufficiently close under a prespecified acceptable range. A high p-value from a difference test does not by itself answer that equivalence question.

The crossover design is also statistically important. When the same participants contribute information under both formulations, paired measurements can contain information that is absent from separate group means and standard deviations. An analysis that accounts for within-participant correlation may differ in precision from a simple comparison of independent summaries. The registry’s sponsor analysis is reported as ANOVA, but the record does not provide enough model detail to evaluate how the crossover structure was represented.

The primary result also shows why confidence intervals deserve attention alongside point estimates. The recalculated interval spans zero and values on both sides, so the point estimate alone does not communicate the uncertainty. For an equivalence question, the interval must be compared with the prespecified equivalence bounds; those bounds are not reported in the registry record.

Finally, the record distinguishes a trial’s observed results from planning calculations. The sample-size illustrations are based on the observed effect under stated assumptions and are not the original design rationale. Keeping those concepts separate prevents an illustrative planning table from being mistaken for evidence about the trial’s planned or achieved power.

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 registry record leaves important information unavailable for independent statistical assessment. It does not report the prespecified equivalence margin, the complete decision rule, or a detailed specification of the sponsor’s ANOVA. The reported geometric ratio and 90% confidence interval can therefore be described, but not fully checked against the criterion for bioequivalence.

The recalculation uses posted summary statistics and is unadjusted. It cannot reproduce a paired crossover analysis, account for within-participant covariance, or evaluate period and sequence effects. The record does not explain how those design features were handled in the sponsor’s model or whether carryover was assessed. The recorded washout phase of at least 5 days does not, on its own, establish that carryover was absent.

Enrollment is listed as 50, while the primary outcome summaries show 40 observations for each formulation. The reason for that difference, the PKS inclusion rules, missing observations, and exclusions are not reported in the registry record. The original sample-size justification and interim-analysis details are also not reported.

The study was open-label and conducted in healthy volunteers. The endpoint is pharmacokinetic exposure, not a clinical outcome, and the registry does not establish how results would translate to other populations or longer-term use. Secondary outcomes are numerous, while a multiplicity procedure is not reported. Safety information is limited to posted counts; detailed timing, event descriptions, and attribution are not provided.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study in Healthy Volunteers to Prove That Two Different Formulations of Rotigotine Patches Deliver Equivalent Drug Amount to the Body — NCT01059903.
• Registry record last updated 2012-05-22; status last verified 2012-05.
• Results first posted 2011-03-03.
• 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

This completed phase 1 study randomized healthy volunteers in an open-label, single-site crossover comparison of rotigotine patch formulations PR2.2.1 and PR2.1.1. Each formulation was applied as a 4.5 mg/10 cm2 patch in opposite treatment orders, with a washout phase of at least 5 days.

The primary outcome was AUC(0-tz) of unconjugated rotigotine. The posted arithmetic means were 5.27 and 5.472 ng/ mL*h, and the unadjusted recalculation estimated a mean difference of 0.202 with a 95% confidence interval from -1.038 to 1.442. The sponsor reported an ANOVA of the ratio of geometric LS-means with a 90% confidence interval.

The registry does not report the equivalence margin, complete model specification, or reasons for the difference between enrollment and primary outcome counts. The results describe pharmacokinetic measurements in healthy volunteers and should not be interpreted as clinical efficacy evidence.