A Study of Rotigotine Patch in Adolescent Subjects With Restless Legs Syndrome of Unknown Cause: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Rotigotine Patch in Adolescent Subjects With Restless Legs Syndrome of Unknown Cause (NCT03728933), a randomized phase 3 study. The primary outcome is Change From Baseline to the End of the Maintenance Period in International Restless Legs Rating Scale (IRLS) Sum Score.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, parallel-group, placebo-controlled study in adolescents with idiopathic RLS. The title describes the study as remote. The registry record reports quadruple masking and states that placebo participants received matching patches to maintain blinding. It does not specify the allocation ratio or the roles encompassed by quadruple masking.

The study focused on rotigotine transdermal treatment during a 12-week maintenance period. Participants assigned to the 2 mg/24h arm were initiated at 1 mg/24h and up-titrated to a maximum of 2 mg/24h. Participants assigned to the 3 mg/24h arm were also initiated at 1 mg/24h and up-titrated to a maximum of 3 mg/24h. Placebo participants received matching patches. The intervention listing names rotigotine 1 mg/24h and 2 mg/24h, whereas the arm descriptions and primary results include a 3 mg/24h arm. This difference in how the interventions and arms are listed is a record-level ambiguity.

The registry reports enrollment of 23 and a terminated study status. The study start date is 2018-12-20, and the primary completion date is 2022-07-25. The reason for termination, the timing of that decision, and whether it affected recruitment, follow-up, or reporting are not reported in the registry record. A protocol rationale for the doses, target enrollment, or duration is also not reported. These details matter when interpreting how closely the completed study reflects the intended design.

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: The Participant Flow refers to the Randomized Set.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set (FAS) consisted of all participants from the Safety Set who had a valid IRLS score and a valid clinical global impressions (CGI) Item 1 score at Baseline and a valid post-Baseline IRLS score and a valid post-Baseline CGI Item 1 score. Here, Number of Participants analyzed signifies those who were evaluable for this outcome measure.

5. Baseline Characteristics

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

Population: The Randomized Set consisted of all participants from the Enrolled Set who have been randomized.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline to the End of the Maintenance Period in International Restless Legs Rating Scale (IRLS) Sum Score, measured over From Baseline to the end of the Maintenance Period (Day 106).

The primary endpoint was change from baseline to the end of the maintenance period in the IRLS sum score, measured at Day 106. The IRLS contains 10 questions, each scored from 0, meaning not present, to 4, meaning very severe. The summed score ranges from 0, no RLS symptoms present, to 40, maximum severity across symptoms. The registry describes scores from 1 to 10 as mild, 11 to 20 as moderate, 21 to 30 as severe, and 31 to 40 as very severe.

Change scores express how the measured score shifted from baseline during the study period. A negative change indicates improvement; a positive change would indicate worsening. This measure is used to quantify symptom severity on a common scale and to summarize change over time. The reported endpoint is continuous, and the results summarize each arm with a mean and standard deviation. A group mean describes the average change, while the standard deviation describes the spread of individual changes around that mean. Neither summary alone indicates whether differences between randomized arms are statistically distinguishable.

The registry also lists change in the RLS-6 rating scales as a secondary outcome. The primary endpoint's analysis population required valid baseline and post-baseline IRLS and CGI Item 1 scores. Details beyond that definition are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General: A randomized parallel-group design assigns participants to separate intervention groups and compares outcomes across those groups. Randomization is intended to reduce systematic differences between groups at the point of assignment, while masking can reduce the influence of expectations on care or outcome assessment. These design features do not remove uncertainty from a small study, and they do not replace reporting the actual between-group analysis.

What do the arm summaries describe?

The primary endpoint is a continuous score change. The reported statistic is the mean change in each arm, accompanied by a standard deviation. A mean gives a central summary of the observed changes. A standard deviation describes how dispersed those changes are around the mean; a larger value indicates more spread in the observed data. The standard deviation is not the uncertainty around a treatment comparison. In particular, it should not be read as a confidence interval or as evidence about statistical significance.

For this endpoint, the arm means are -8.2 for placebo, -14.0 for rotigotine 2 mg/24h, and -6.4 for rotigotine 3 mg/24h. Since a negative change indicates improvement, these summaries describe reductions in mean scores within all three arms. A randomized treatment effect is instead a contrast between outcomes in assigned groups. The registry record does not post such a contrast, its standard error, a confidence interval, or a test result. No new contrast should be inferred from the arm means alone.

What would a confidence interval add?

General: A confidence interval expresses uncertainty around an estimated quantity, such as a mean difference between groups. Its width reflects both the variability in the data and the amount of information available under the analysis assumptions. A narrow interval indicates greater precision than a wide one, but an interval does not by itself establish clinical importance. No confidence interval for a between-arm effect is reported in the registry record, so the precision of any treatment contrast cannot be assessed from these posted results.

How should the planned sample-size illustrations be read?

General: A sample-size calculation is a planning exercise based on assumptions about the effect to detect, outcome variability, allocation, significance level, and statistical method. It estimates the number of participants needed under those assumptions; it does not show what effect was observed or how likely the completed trial was to produce a significant result. The planning illustration associated with the posted results is based on the observed effect, uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It considers detecting a stated fraction of the observed effect. These calculations are illustrations, not the trial's reported design justification and not observed power. The registry record does not report the trial's own sample-size rationale.

Because the trial has three arms, a two-arm planning illustration should not be mistaken for a complete analysis of the study design. The record does not report a prespecified primary contrast, a method for handling multiple comparisons, or a model used for the primary endpoint. Nor does it report an adjustment for baseline score or other covariates. These methods should not be presumed from the arm summaries.

What does a missing comparative analysis mean?

The registry reports zero posted analyses. The result values are descriptive arm-level summaries, not a set of inferential tests. The record indicates that values were missing or not estimable for a two-arm comparison of the continuous endpoint. Consequently, there is no posted estimate with which to judge the direction and precision of a direct rotigotine-versus-placebo contrast. General: When data are sparse, estimates may be unstable and intervals may be wide; this is a reason to report uncertainty, not a basis for replacing it with a conclusion from separate group means.

The posted summary also gives analyzed participant counts and standard deviations. These allow a basic description of the endpoint but do not reveal the distribution of individual scores, the handling of missing observations, or whether assumptions underlying any model were assessed. Those details are not reported in the registry record. Any further statistical interpretation would require information not contained in the posted record.

10. Confidence Intervals for Each Arm

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

R code and output

arm <- c("Placebo", "Rotigotine 2 mg/24h", "Rotigotine 3 mg/24h")
n   <- c(5, 7, 5)
m   <- c(-8.2, -14, -6.4)
sp  <- c(6.8, 8.2, 5.8)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Placebo  5  -8.200  6.800  -16.643  0.243
CARM  Rotigotine 2 mg/24h  7  -14.000  8.200  -21.584  -6.416
CARM  Rotigotine 3 mg/24h  5  -6.400  5.800  -13.602  0.802

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary IRLS change outcome and a secondary outcome concerning change in RLS-6 rating scales. It also reports five outcome measures, but only one secondary outcome is named in the posted secondary-outcome listing. The record does not report a multiplicity strategy, such as a hierarchy among outcomes or an adjustment for testing multiple hypotheses. Without that information, the error rate intended for a family of comparisons is not known. No p-values or comparative analyses are posted, so the registry results do not show how multiplicity was addressed in any inferential testing.

The primary analysis population is described as the Full Analysis Set. It included participants from the Safety Set who had valid IRLS and CGI Item 1 scores at baseline and valid post-baseline IRLS and CGI Item 1 scores. This definition indicates that validity of both measures at both time points was required for inclusion in the described population. The registry record does not state how many participants were excluded from the primary analysis for not meeting these requirements, nor does it report missingness by arm or the reasons for missing measurements.

Methods for handling missing outcome data are not reported in the registry record. It is therefore unknown whether missing values were imputed, handled by a model, or omitted from the endpoint analysis beyond the stated Full Analysis Set eligibility definition. The record also does not report sensitivity analyses assessing how alternative assumptions about missing data might affect results. The enrollment figure and the analyzed arm counts refer to different aspects of the study record; the available information does not explain all participant flow from enrollment through analysis.

These reporting gaps limit assessment of whether the posted means represent all randomized participants or a selected subset, and whether missing data could have affected arm comparisons. They also prevent evaluation of the intended inferential plan. No assumptions about the protocol, analysis populations beyond the stated definition, or interim analyses can be established from the registry record.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: type 2 diabetes mellitus (14.3%).

The safety results report serious adverse events for participants at risk in each arm. The placebo group had 0 serious adverse events among 8 at risk; the rotigotine 2 mg/24h group had 0 among 8 at risk; and the rotigotine 3 mg/24h group had 1 among 7 at risk. The listed serious-event term was Type 2 diabetes mellitus (14.3%). The registry record does not state whether that event was considered related to study treatment, and the term should not be interpreted as evidence of causation.

The record reports 7 participants affected by other adverse events among 8 at risk in the placebo arm, 7 among 8 at risk in the rotigotine 2 mg/24h arm, and 5 among 7 at risk in the rotigotine 3 mg/24h arm. Deaths were reported as 0 in each arm. These counts describe events recorded in the registry; they do not establish comparative safety, especially without fuller event definitions, timing, severity, exposure information, or an inferential comparison.

The safety denominators differ from the analyzed counts for the primary endpoint. They refer to participants at risk for the safety summaries, not necessarily the population used for the IRLS analysis. The registry record does not provide additional detail about adverse-event collection or adjudication. These figures are descriptive and should be read alongside the limitations of the small analyzed groups and incomplete reporting.

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

The posted primary results describe changes in IRLS scores in three randomized arms during the study period. The mean change was negative in the placebo arm and in both rotigotine arms, which means each arm's mean score moved in the direction designated as improvement by the registry. The observed means and standard deviations characterize the available analyzed participants; they do not answer the randomized comparison on their own.

The key distinction is between change within an arm and a difference between arms. A within-arm change can reflect multiple influences over time, including the course of symptoms and study participation, as well as any treatment effect. The placebo group provides a randomized comparator, but the registry record does not post an estimated difference between placebo and either rotigotine dose. It also does not report confidence intervals or p-values for such comparisons. The relative magnitude and precision of a treatment effect therefore cannot be established from the available results.

The arm-level summaries do not show how individual participants responded or whether the group means describe a uniform pattern. Standard deviations indicate variation, but they do not identify the range of individual outcomes or the proportion of participants who improved. The record also does not report enough information to assess missing-data effects, the reason for termination, or the influence of termination on the analysis.

The safety counts are similarly descriptive. They record serious and other adverse events by arm, but do not establish whether an event was caused by treatment or whether observed counts differ beyond chance. The reported serious-event term and percentage should be interpreted as a registry listing, not as a causal finding.

Accordingly, the posted evidence allows a description of the observed scores and adverse-event counts, but not a definitive estimate of comparative efficacy or safety. It does not establish whether rotigotine changed symptoms more or less than placebo, nor how certain such a difference would be. No medical conclusion should be drawn from these arm summaries alone.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between posting outcome summaries and reporting a complete treatment comparison. A randomized design is intended to make a between-group contrast meaningful, but readers need the contrast itself, together with an estimate of its uncertainty, to judge what the data say about the primary question. Here, the registry record supplies arm means, standard deviations, and analyzed counts, but no comparative analysis, confidence interval, or p-value.

The score's direction is also important for interpretation. Negative change indicates improvement, and all three posted arm means are negative. That observation shows why an active-arm change should not be interpreted in isolation: the placebo arm also had a negative mean change. The relevant question is how outcomes differed between assigned groups, and the record does not provide that estimate.

The study status and analysis population add context. The record reports termination and an enrollment of 23, while the primary endpoint summaries are based on small arm-level analyzed groups. The reason for termination and participant flow are not reported in the registry record. Without these details, it is difficult to assess how the available results relate to the study's intended conduct and whether missing outcomes could affect interpretation.

Finally, the record illustrates why statistical planning displays should be kept separate from trial findings. A sample-size illustration based on an observed effect is not the trial's original design rationale and does not establish observed power. The registry does not report its own sample-size justification or a complete inferential plan. Clear distinctions among observed summaries, comparative estimates, uncertainty, and planning assumptions are essential for interpreting this kind of clinical trial record.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpreting the primary result is the absence of a posted between-arm estimate. The registry provides means and standard deviations by arm, but no effect contrast, confidence interval, or p-value. A treatment effect and its precision cannot therefore be evaluated directly from the posted results. Separate arm means should not be treated as a substitute for the randomized comparison.

The analyzed group sizes are small: the primary endpoint summaries include 5 participants in the placebo arm, 7 in the rotigotine 2 mg/24h arm, and 5 in the rotigotine 3 mg/24h arm. With limited observations, group summaries may be sensitive to individual outcomes. The registry does not provide participant-level results or additional distributional details. The reason for the study's terminated status is not reported, so its possible effect on enrollment, follow-up, or analysis cannot be assessed.

There are also reporting ambiguities. The intervention listing names rotigotine 1 mg/24h and 2 mg/24h, while the arm descriptions and outcome results include rotigotine 2 mg/24h and 3 mg/24h. The record does not explain this difference. It does not report the allocation ratio, the primary statistical model, a prespecified comparison, multiplicity handling, or methods for missing outcome data. The Full Analysis Set definition requires valid baseline and post-baseline IRLS and CGI Item 1 scores, but the number and reasons for exclusions are not given.

Safety results are presented as counts, without enough detail to establish treatment attribution or support a comparative safety analysis. The registry record also does not report the trial's sample-size rationale or any interim analyses. These limitations do not negate the descriptive results, but they constrain the conclusions that can be drawn about comparative outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Rotigotine Patch in Adolescent Subjects With Restless Legs Syndrome of Unknown Cause — NCT03728933.
• Registry record last updated 2023-10-26; status last verified 2023-09.
• Results first posted 2023-10-26.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry describes NCT03728933, a Phase 3 randomized, parallel-group study of rotigotine patches versus matching placebo in adolescents with idiopathic RLS. It reports quadruple masking, remote study conduct in the title, enrollment of 23, and terminated status. The recorded start date is 2018-12-20, and primary completion is dated 2022-07-25.

The primary endpoint was change in IRLS sum score from baseline to Day 106. The posted mean changes were -8.2 for placebo, -14.0 for rotigotine 2 mg/24h, and -6.4 for rotigotine 3 mg/24h. No comparative analyses are posted. The registry also lists change in RLS-6 rating scales as a secondary outcome and reports adverse-event counts by arm.

The registry record does not report the reason for termination, the primary comparison method, missing-data methods, or the sample-size rationale. These omissions, together with the absence of comparative estimates and uncertainty intervals, limit conclusions about treatment differences.