Cardiac Effects of Rotigotine Transdermal System in Subjects With Advanced-stage Idiopathic Parkinson's Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cardiac Effects of Rotigotine Transdermal System in Subjects With Advanced-stage Idiopathic Parkinson's Disease (NCT00292227), a randomized phase 1 study. The primary outcome is Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTc Based on the QTcI at Time of Patch Application on Day 42 (Rotigotine Dose of 54 mg/Day) (Parallel-group Comparison).

2. Clinical Question

The registry's stated purpose was to assess whether rotigotine affects cardiac electrical activity. The positive-control infusion comparisons had a related but separate role: moxifloxacin infusion was included to assess assay sensitivity. That control comparison should not be confused with the primary patch comparison, which addresses the difference in QTcI change between rotigotine and placebo patches.

3. Trial Design

The registry record describes NCT00292227 as a randomized, triple-masked, parallel-group Phase 1 trial. It lists an enrollment of 130 and a status of completed. The trial concerned people with advanced-stage idiopathic Parkinson's disease and was sponsored by UCB Pharma. The recorded start was 2006-01 and primary completion was 2006-09.

For the primary comparison, participants received either a rotigotine patch or a placebo patch. The primary endpoint compared groups rather than following each participant through a patch-treatment crossover. Moxifloxacin infusion and placebo infusion were included for separate cross-over comparisons at scheduled time points. The registry's brief summary identifies moxifloxacin as the positive control used to assess assay sensitivity.

The primary outcome was a continuous measure: time-matched change from baseline in QTcI, expressed in milliseconds. Baseline was the average of ECG assessments on Day -2 and Day -1, with baseline and final measures taken at 20:00h. The endpoint compared the groups at the time of patch application on Day 42, for rotigotine at 54 mg/day. The primary analysis population was described as the safety population, and only non-missing values were analyzed.

The registry record does not report the planned allocation ratio, details of the randomization procedure, or the specific masking roles covered by triple masking. It also does not report the trial's original sample-size assumptions or a detailed protocol-level statistical plan. Those omissions limit what can be concluded about the intended design beyond the registered randomized, masked, parallel-group structure and the outcomes described in the 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.

Before assignment: Within the placebo patch group, subjects were randomized to the sequence of receiving either placebo saline iv solution or moxifloxacin iv solution on Days 32 and 39 in a cross-over design. This treatment was in addition to treatment with the placebo patch. Subjects in the rotigotine patch group received placebo iv solution on Day 32 and Day 39.

Patch Period

Reasons for not completing this period:

Cross-over Period 1 (Day 32)

Cross-over Period 2 (Day 39)

Analysis population for the primary outcome, as defined in the registry: Safety population; only non-missing values were analyzed.

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 Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTc Based on the QTcI at Time of Patch Application on Day 42 (Rotigotine Dose of 54 mg/Day) (Parallel-group Comparison), measured over Baseline (Day -2/ Day -1) 20:00h, Day 42 20:00h.

The primary endpoint measures the change in the heart's QT interval, corrected for heart rate using an individualized formula, from baseline to the scheduled assessment on Day 42. The QT interval is measured on an electrocardiogram. Because heart rate can affect the observed QT interval, the registry describes use of QTcI, an individualized correction that includes QT/RR curvature optimization. The outcome is reported in milliseconds, with group means and standard deviations.

For this endpoint, baseline QTcI was the average of the ECG assessments on Day -2 and Day -1. The time-matched comparison used the assessment at 20:00h on Day 42, at the time of patch application, for the 54 mg/day rotigotine dose. Change from baseline helps express how the measured value at the scheduled assessment differs from the participant's baseline value; comparing the groups addresses whether their average changes differed during the trial.

QTcI is used as an electrocardiographic measure for assessing potential effects on cardiac electrical activity. It is not a direct measure of symptoms, daily function, or Parkinson's disease progression. The endpoint's clinical interpretation depends on how large and precise the group difference is, and on the relevance of that difference to cardiac risk. The registry record does not report a threshold for clinical importance or a decision rule for interpreting the QTcI difference.

7. Results Posted in the Registry

• Rotigotine Patch: mean 0.46 versus 1.13 on control; difference -0.67 (95% CI -2.92 to 1.58), standardized effect d = -0.10; z-test p = 0.559.

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.

Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 2 Hours Before Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)

• 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:
  • Moxifloxacin Infusion: mean 1.70 versus 1.29 on control; difference 0.41 (95% CI -1.78 to 2.60), standardized effect d = 0.07; z-test p = 0.713.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Moxifloxacin Infusion and the control. The interval gives the range of effects that remain compatible with the data.

Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 1 Hour Before Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)

• 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:
  • Moxifloxacin Infusion: mean 1.84 versus 1.36 on control; difference 0.48 (95% CI -1.65 to 2.61), standardized effect d = 0.08; z-test p = 0.659.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Moxifloxacin Infusion and the control. The interval gives the range of effects that remain compatible with the data.

Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI at Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)

• 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:
  • Moxifloxacin Infusion: mean 2.21 versus 0.82 on control; difference 1.39 (95% CI -1.03 to 3.81), standardized effect d = 0.20; z-test p = 0.261.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Moxifloxacin Infusion and the control. The interval gives the range of effects that remain compatible with the data.

The registered secondary QTcI outcomes include time-matched infusion comparisons involving moxifloxacin as the positive control and placebo infusion as the corresponding control. The purpose differs from the primary patch comparison: the infusion analyses address assay sensitivity and describe QTcI at scheduled times around infusion. The registry lists multiple secondary outcomes, with 13 secondary results posted.

Across the detailed secondary comparisons, the unadjusted recalculated mean differences are positive, but their confidence intervals include zero. The sponsor's reported ANOVA estimates also vary in their interval relationship to zero. This means the detailed secondary results do not form a uniformly precise pattern under both approaches. The results are consistent with the intended role of a positive control being assessed, but the registry record does not provide a formal overall conclusion about assay sensitivity or the prespecified criteria for that judgment.

These secondary findings do not replace or directly settle the primary patch comparison. They involve infusion conditions and cross-over comparisons, whereas the primary endpoint compares rotigotine patch with placebo patch in a parallel-group design. Their results may provide context about the ECG measurement process, but should not be treated as evidence of the primary patch effect.

Secondary outcomes typically carry less inferential weight when many outcomes, times, or comparisons are examined without a reported multiplicity plan. Repeated testing increases the chance that an apparently notable result arises by chance. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting the secondary outcomes. Accordingly, individual secondary comparisons are best read as supportive and exploratory unless a prespecified testing strategy is documented.

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

• Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 2 Hours Before Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)
• Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 1 Hour Before Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)
• Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI at Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)
• Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 1 Hour After Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)
• Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 2 Hours After Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)
• Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 3 Hours After Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)
• Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 4 Hours After Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)
• Time-matched Change From Baseline (Average of Day -2 and Day -1) in QTcI 5 Hours After Start of Infusion on Day 32 or Day 39 (Positive Control) and Respective Day 39 or Day 32 (Corresponding Placebo) (Cross-over Comparison)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: each analyzed participant has a change in QTcI measured in milliseconds, and the registry reports a mean and standard deviation for each patch group. A mean describes the average observed change. A standard deviation describes how spread out individual values are around that group mean. The standard deviation is not the uncertainty in the group mean or in the difference between groups; those uncertainties are represented by standard errors and confidence intervals in the recalculated comparison.

What does the group comparison estimate?

The main contrast is the difference in average change between the rotigotine patch group and the placebo patch group. In the unadjusted recalculation, the estimate is -0.67 milliseconds. The sign reflects the order of the comparison: rotigotine relative to placebo. A negative estimate means the observed average change was lower in the rotigotine group. It does not, on its own, say whether the difference is important or whether the treatment has a beneficial or harmful clinical effect.

The recalculation is unadjusted and based on the posted summary statistics. It does not reproduce the sponsor's ANCOVA model. An adjusted analysis can account for baseline or other model terms if they were specified and included, whereas a simple comparison of group summaries does not. The registry gives the sponsor method as ANCOVA, but the full model specification and covariates are not reported in the registry record. Therefore, the recalculated estimate is a useful summary check, not a replacement for the sponsor's analysis.

What does a confidence interval convey?

A confidence interval describes the range of estimates compatible with the observed data under the analysis assumptions and method. A narrower interval indicates greater statistical precision; a wider interval indicates more uncertainty about the size and direction of the difference. For the unadjusted recalculation, the 95% confidence interval runs from -2.92 to 1.58 milliseconds. Because it includes zero, the results do not distinguish a difference from no difference at that confidence level. The interval also includes values on both sides of zero, so the data do not pin down the direction with high precision.

A confidence interval is not a statement that a particular probability applies to the fixed true effect after the analysis. It also does not identify which values are clinically important. That requires a clinical threshold or interpretation framework, which is not reported in the registry record. Statistical compatibility with zero should not be recast as proof that the groups are equivalent.

Why use an individualized QT correction?

As a general statistical and measurement point, heart rate can influence the QT interval observed on an ECG. A correction aims to make QT measurements more comparable across heart rates. The registry describes QTcI as an individualized correction formula that includes QT/RR curvature optimization. Individualized correction is intended to reflect a participant's QT and RR relationship rather than applying only a single correction across all participants. This description explains the measure; it does not establish that all measurement or modeling assumptions were met in the trial.

The endpoint compares change from a baseline average with a scheduled value at the same clock time, 20:00h. Time matching is a way to align the measurement times used in the change comparison. The registry identifies the ECG baseline as the average from Day -2 and Day -1, and the endpoint assessment as Day 42 at the time of patch application. Further details about ECG acquisition, repeat readings, or handling of measurement variability are not reported in the registry record.

How does the positive control fit?

The moxifloxacin infusion comparisons are separate cross-over analyses, not additional arms in the primary parallel-group patch comparison. The registry says the infusion was used as a positive control to assess assay sensitivity. As a general concept, a positive control is included to check whether a study measurement and analysis can detect a known or expected signal under the study conditions. The record identifies the purpose, but does not report the full criteria for judging assay sensitivity or the prespecified analysis rules for that assessment.

The registered secondary outcomes describe time-matched QTcI changes at several points around the infusion and their corresponding placebo infusion comparisons. Such scheduled measurements can describe the timing of an electrocardiographic response. They do not alter the definition of the primary patch endpoint, and the secondary comparisons should be interpreted with their own analysis methods and uncertainty.

What is not established by these methods?

The registry record does not report a full prespecified statistical analysis plan, a clinical-importance threshold, the ANCOVA covariates, or the rationale for the analysis populations. It does not report whether interim analyses were planned or conducted. These details should not be inferred from the posted means, confidence intervals, or the classification of the sponsor analysis. The estimates support a description of the recorded outcome and its uncertainty, rather than an unrestricted conclusion about cardiac effects.

11. Confidence Intervals and Precision

The simple unadjusted recalculation estimates a mean difference of -0.67 milliseconds, with a 95% confidence interval from -2.92 to 1.58. This interval spans zero and includes estimates in both directions. It therefore shows that the observed difference is not estimated with enough precision to establish a clear direction using this interval alone. The width also indicates meaningful uncertainty about the size of the difference. The registry record does not state which values would be clinically negligible or important.

The sponsor's ANCOVA estimate is -0.75 milliseconds, with a 90% confidence interval from -2.63 to 1.12. This is a different analysis and confidence level from the recalculation, so the intervals should not be treated as interchangeable. Both intervals include zero, and their estimates are close in direction and magnitude. The sponsor analysis is the registered analysis; the recalculation is an unadjusted comparison from posted summary statistics.

Confidence intervals are useful because a point estimate alone can make an uncertain result look definitive. Here, the interval for the recalculation allows a range of possible differences around the estimate. It is not evidence that every value in the interval is equally plausible, and it is not a probability statement about the true effect. It also does not establish equivalence. A formal equivalence interpretation requires prespecified limits, which are not reported in the registry record.

The precision is affected by both the amount of information in the analyzed groups and the observed variability. The registry reports standard deviations of 5.96 and 6.86 milliseconds for the two groups, while the primary analysis includes the non-missing values from the safety population. The record does not provide a clinical threshold against which to judge whether the confidence interval is sufficiently narrow for a practical conclusion.

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 participants per arm, not total participants and not total events. This is a continuous-outcome comparison, so the figures describe participants needed in each of two equally allocated arms under the stated planning assumptions. The registry record's planning illustration uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It sets the effect to detect at the stated fraction of the observed effect: 100%, 75%, or 50%.

The 80% power column means the illustrated per-arm sample size for a design with an 80% chance of detecting the specified effect under those assumptions, if that effect and the model assumptions hold. The 90% power column gives the corresponding planning size for a 90% chance. These are planning targets, not a description of the probability that the completed trial found an effect. This is not observed power.

The rows that plan for 100% of the observed effect use the observed estimate as the target effect. Planning for 75% or 50% of the observed effect asks for a smaller effect to be detectable. Smaller effects require more participants because they are harder to distinguish from the background variability. For the primary comparison, the per-arm figures rise as the target fraction decreases: the listed 80% power values are 1,438, 2,556, and 5,750, and the listed 90% power values are 1,925, 3,421, and 7,698, respectively.

These calculations are illustrative and are not the trial's original design justification. The original sample-size assumptions are not reported in the registry record. The planning values use the observed effect and specified statistical assumptions, so they should not be read as evidence that the completed study was adequately or inadequately powered under its original design.

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 = -0.670; pooled standard deviation σ = 6.411.
2. n = 2 × (1.96 + 0.842)² × 6.411² / -0.670² = 1,437.4, rounded up to 1,438 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 <- -0.67                      # observed difference in means
sigma <- 6.41127937511745                     # 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(292227)
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 = 1,438 (80% power), 1,925 (90% power)
 75% of observed effect: n per arm = 2,556 (80% power), 3,421 (90% power)
 50% of observed effect: n per arm = 5,750 (80% power), 7,698 (90% power)
power.t.test: 1438.4 
Simulated power at n = 1,438 per arm: 0.803 (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 ANCOVA estimate of a net mean difference of -0.75 milliseconds, with a 90% confidence interval from -2.63 to 1.12. The registry does not give a p-value for this analysis. The interval includes zero, so it does not establish a difference from zero under the reported interval. The record classifies this analysis as noninferiority or equivalence, but the margin and formal decision criteria are not reported; the classification alone is not enough to conclude equivalence or noninferiority.

The unadjusted recalculation from the posted group summaries estimates a mean difference of -0.67 milliseconds, with a 95% confidence interval from -2.92 to 1.58 and an unadjusted p-value of 0.559. Its estimate is close to the sponsor's in direction and magnitude, but the methods and confidence levels differ. ANCOVA may incorporate model terms not present in a simple comparison; the registry does not report the complete model specification.

The recalculation is a check based on summary statistics, not a reconstruction of the sponsor's analysis. There is no reported discrepancy between the recalculation and sponsor estimate. The sponsor's analysis remains the trial's reported analysis, while the recalculation provides a transparent, unadjusted view of the posted group results.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists 38 outcome measures and 38 analyses, and 13 secondary results are posted. The secondary ECG outcomes include several time points and infusion comparisons. When many outcomes or time points are examined, the chance of at least one seemingly notable result can increase. Statistical methods can address this through adjustment or a prespecified hierarchy, but the multiplicity strategy is not reported in the registry record. Without that information, individual secondary results should not be interpreted as if they were the sole planned test.

The primary endpoint is identified separately from the secondary outcomes, which helps distinguish the main registered question from additional measurements. However, the record does not provide enough information to establish the full testing hierarchy, whether any secondary findings were confirmatory, or whether multiplicity was considered in the sponsor's analyses. The reported p-value for the recalculation is unadjusted and should be interpreted as such.

For the primary endpoint, the registry says the analysis used the safety population and included only non-missing values. The record does not report how many eligible participants lacked primary endpoint measurements, why any values were missing, or how missingness was handled beyond analyzing non-missing values. It also does not report an imputation or sensitivity analysis for missing primary values. Missing data can affect an estimate if the availability of measurements is related to participants' outcomes or group assignment; the direction and size of any such effect cannot be determined from the registry record.

The sample size in the trial record is an enrollment figure, while the primary group summaries report the numbers with non-missing outcome values. The registry does not describe the full analysis populations for each secondary outcome or provide participant flow details in the registry record recorded for this analysis. It also does not report interim analyses, stopping rules, or the complete statistical analysis plan. These gaps limit assessment of how planned analyses, missing data, and multiple testing were handled.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: syncope (1.6%).

The safety record reports serious adverse events for the patch groups. In the rotigotine patch group, 0 of 66 participants at risk were recorded as affected by a serious adverse event. In the placebo patch group, 1 of 64 participants at risk was recorded as affected. Syncope is listed as the top serious adverse event term, at 1.6%.

These figures describe the recorded serious adverse event counts and the stated at-risk groups. They do not by themselves establish whether the groups differ in safety, particularly given the limited event counts and the absence of a reported comparative safety analysis in the registry entries. The registry does not report deaths for these groups; the death figures are not reported in the registry record.

The record also lists other adverse events as affecting 63 of 66 participants in the rotigotine patch group and 54 of 64 in the placebo patch group. Serious and other adverse events are distinct categories in the registry. These safety summaries are not the same as the primary ECG endpoint and should not be used to infer the cardiac meaning of the QTcI comparison.

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

The primary result estimates the difference between rotigotine patch and placebo patch in mean change in QTcI at the scheduled Day 42 assessment. The unadjusted recalculation is -0.67 milliseconds, and its 95% confidence interval includes zero. The sponsor's ANCOVA estimate is similar in direction and magnitude, and its 90% confidence interval also includes zero. Together, these results describe a small estimated difference with uncertainty that does not establish a clear difference from zero.

This does not prove that the groups were identical or that rotigotine has no effect on cardiac electrical activity. A confidence interval that includes zero can be compatible with no difference and with nonzero differences. Formal evidence of equivalence or noninferiority requires a prespecified margin and decision criteria; those are not reported in the registry record, despite the sponsor analysis being classified under noninferiority or equivalence.

Nor does the result establish that rotigotine causes a clinically meaningful cardiac effect. The registry provides no clinical-importance threshold for the QTcI change and no broader clinical cardiac outcome in the registry record analyzed. QTcI is an electrocardiographic measure, not a direct measure of symptoms or long-term clinical consequences. The endpoint should therefore be interpreted within its defined population, dose, measurement method, and assessment time.

The positive-control infusion analyses address assay sensitivity, a distinct aim from the primary patch comparison. They do not transform the primary estimate into a treatment-efficacy finding or resolve its uncertainty. The registry record supports a description of observed ECG changes and their statistical precision, but not medical advice or a conclusion about treatment decisions.

18. Why This Trial Matters Statistically

This trial is statistically useful because its central question concerns measurement and interpretation of an electrocardiographic outcome, not a symptom score or clinical event. It illustrates how a clinical study can define a continuous endpoint, align measurements to baseline and follow-up times, and compare group means while accounting for the need to correct QT intervals for heart rate.

The randomized, triple-masked, parallel-group design gives the primary patch comparison a clear structure: rotigotine patch is compared with placebo patch at a specified dose and assessment time. Separately, the positive-control infusion comparisons show why a study may include a control intended to assess whether the measurement system can detect a signal. Keeping these distinct comparisons separate is important when interpreting their estimates.

The result also illustrates why an estimate should be read alongside its confidence interval. The recalculated mean difference is close to zero, but its interval covers values on both sides of zero. That uncertainty is more informative than treating a single p-value as a definitive verdict. Likewise, a classification of noninferiority or equivalence cannot be fully assessed without the relevant margin and analysis criteria.

Finally, the record highlights the limits of registry reporting for statistical interpretation. The primary outcome and sponsor analysis are described, but details such as the complete model specification, multiplicity strategy, missing-data sensitivity analyses, and original sample-size rationale are not reported. Recognizing these boundaries helps distinguish what the posted estimates show from what would require additional protocol or analysis information.

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 available primary outcome is a time-specific QTcI change at Day 42 for a rotigotine dose of 54 mg/day. It does not provide evidence about other doses, other assessment times, or longer-term cardiac outcomes. The registry record does not report a clinical-importance threshold for the endpoint, so the practical significance of the estimated difference cannot be judged from the statistical results alone.

The primary group summaries include 65 rotigotine patch participants and 61 placebo patch participants with non-missing values. The registry identifies the safety population but does not report the number or reasons for missing primary endpoint values, nor a missing-data sensitivity analysis. It is therefore not possible to assess from this record whether missing measurements could affect the comparison.

The sponsor reports an ANCOVA estimate, but the model covariates and full specification are not reported in the registry record. The recalculation is unadjusted and cannot substitute for a complete reanalysis. In addition, the sponsor analysis is classified as noninferiority or equivalence, while the margin and formal criteria are not reported. That limits assessment of what formal conclusion the sponsor intended the analysis to support.

The trial includes multiple secondary outcomes and time points, but the multiplicity strategy and testing hierarchy are not reported. The positive-control analyses are described as assessing assay sensitivity, but the formal criteria for that assessment are not available in the record. Finally, the sample-size planning illustration is based on the observed effect and is not the original trial design justification; the original sample-size assumptions are not reported in the registry record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Cardiac Effects of Rotigotine Transdermal System in Subjects With Advanced-stage Idiopathic Parkinson's Disease — NCT00292227.
• Registry record last updated 2014-10-27; status last verified 2011-02.
• Results first posted 2010-02-04.
• 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

NCT00292227 is a completed, randomized, triple-masked, parallel-group Phase 1 trial sponsored by UCB Pharma. It studied rotigotine patch versus placebo patch in people with advanced-stage idiopathic Parkinson's disease and assessed potential effects on cardiac electrical activity. The registry records an enrollment of 130, a start of 2006-01, and primary completion in 2006-09.

The primary endpoint was time-matched change from baseline in QTcI at the Day 42 assessment for rotigotine at 54 mg/day. The unadjusted recalculation estimates a mean difference of -0.67 milliseconds, with a 95% confidence interval from -2.92 to 1.58. The sponsor's ANCOVA estimate was -0.75 milliseconds, with a 90% confidence interval from -2.63 to 1.12. Both intervals include zero, and the record does not report a clinical-importance threshold or equivalence margin.

Moxifloxacin infusion was included as a positive control for assay sensitivity, with placebo infusion comparisons reported as secondary outcomes. Interpretation is limited by unreported details of the original sample-size rationale, multiplicity strategy, missing-data handling, and full sponsor model specification.