Study to Investigate Pharmacokinetics (PK) of Pramipexole in Pediatric Patients Who Are Individually Optimized to Stable Pramipexole Doses for the Treatment of Idiopathic Restless Legs Syndrome (RLS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Investigate Pharmacokinetics (PK) of Pramipexole in Pediatric Patients Who Are Individually Optimized to Stable Pramipexole Doses for the Treatment of Idiopathic Restless Legs Syndrome (RLS) (NCT02231918), a non-randomized phase 2 study. The primary outcome is Cmax,ss.

2. Clinical Question

The clinical question is therefore primarily pharmacokinetic: what maximum plasma concentrations were observed in pediatric patients receiving individually optimized, stable pramipexole doses? This differs from a treatment-effect question asking whether pramipexole improves symptoms compared with another treatment or with no treatment. The registry’s primary endpoint is a drug-concentration measure, not a direct measure of restless legs syndrome symptoms.

The study also listed drug-related adverse events, systolic and diastolic blood pressure, and pulse rate as secondary outcomes. The posted adverse-event figures distinguish serious adverse events from other adverse events. However, the record does not report the primary concentration estimates, results for the vital-sign outcomes, or a symptom-effect estimate. The available information can describe the study question and the reported safety counts, but it cannot establish how concentrations differed among dose groups or what clinical effects followed.

3. Trial Design

This was a phase 2, open-label, non-randomized, parallel study sponsored by Boehringer Ingelheim. The registry lists an enrollment of 26 and a completed status. The recorded start was 2006-05, and primary completion was 2007-07. These details describe the registered study; they do not provide evidence about the size or precision of any particular endpoint analysis.

The study examined pramipexole pharmacokinetics in pediatric patients with restless legs syndrome. Its official title specifies oral administration once daily at 0.125 mg, 0.25 mg, and 0.5 mg. The intervention groups are labelled low, medium, and high. The record says patients were individually optimized to stable doses, but the arm descriptions are empty. Further details about how dose assignment or optimization proceeded are not reported in the registry record.

Because allocation was non-randomized and masking was absent, the dose groups should not be treated as randomized comparison groups. Differences between groups, if reported, could reflect factors other than dose, and the record does not describe an adjustment strategy to address such differences. The parallel model indicates separate groups rather than a stated within-person crossover comparison.

The brief summary describes determination of pharmacokinetics after administration of a single oral dose, while the primary endpoint description refers to Cmax at steady state and measurement times around the last administration on day 1. These descriptions are both part of the registry record; further protocol detail resolving how they relate is not reported in the registry record. The record also does not explain the rationale for the enrollment target, the dose allocation process, or whether the study used interim analyses.

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: Open label, single dose pharmacokinetic study in pediatric patients with a diagnosis of idiopathic Restless Legs Syndrome(RLS). For the dose MIRAPEX(0.5 mg),Only 2 subjects (12 to\<18 years) were recruited and it was not likely that patients for this dose will be fully recruited so the recruitment was stopped and terminated for this dose only.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic Set (PK): All evaluable patients who received at least one dose of Pramipexole (PPX) between 0.125 and 0.5 mg were included in the PK analysis.

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: Safety analysis set: The safety population comprised all patients who provided informed consent and received at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Cmax,ss, measured over 0.25h before the drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1..

The primary endpoint, Cmax,ss, is the maximum concentration of pramipexole in plasma at steady state over a uniform dosing interval. It is recorded in ng/mL and summarized using a geometric mean with a geometric coefficient of variation as the dispersion measure. A concentration maximum is used in pharmacokinetic work to describe peak drug exposure during a dosing interval; it is not itself a symptom score or a direct measure of clinical benefit.

The registry specifies blood-sampling times at 0.25h before drug administration on day1 and 0.5 h, 1 h, 2 h, 3 h, 5 h, 7h, 12h and 24h after the last drug administration on day 1. The endpoint description identifies the maximum concentration at steady state, while the brief summary refers to pharmacokinetics after a single dose. The relationship between these descriptions is not further explained in the registry record.

Geometric summaries are commonly used for concentration measurements when values are positive and may be multiplicatively distributed. A geometric coefficient of variation conveys relative dispersion on a multiplicative scale, rather than the absolute spread around an arithmetic mean. These are general statistical interpretations of the stated summaries. The registry record does not report the geometric mean, its coefficient of variation, a confidence interval, or a comparison of endpoint values across dose groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary endpoint represent?

Cmax,ss describes the highest plasma concentration of pramipexole at steady state during a uniform dosing interval. As a pharmacokinetic measure, it summarizes concentration exposure rather than a patient-reported symptom or a clinical event. The registry specifies a geometric mean and geometric coefficient of variation. In general, a geometric mean is useful for positive measurements whose variation is more naturally described in relative or multiplicative terms. The corresponding coefficient of variation describes relative spread, not a raw-unit distance from the mean.

The endpoint’s stated unit is ng/mL, and the record gives blood-sampling times around administration on day 1. The description identifies the maximum concentration, but does not say how any unsampled peak was handled or provide a calculation procedure. That information is not reported in the registry record. The record also does not contain the actual concentration summaries.

Why does the study design matter?

The study is described as non-randomized, open-label, and parallel. In general, random assignment can reduce systematic differences between groups, while masking can reduce some forms of measurement or behavior bias. Neither feature is listed for this study. This does not by itself invalidate pharmacokinetic description, but it limits what can be inferred from between-group contrasts. The three dose groups should not be understood as randomized treatment arms with an assured like-for-like comparison.

Because the design is parallel, the registry does not describe each participant receiving every dose in a crossover sequence. The record does not specify whether analyses adjusted for patient characteristics or other possible sources of group differences. Such statistical methods are not reported in the registry record. General statistical caution is therefore appropriate when interpreting any contrast among the dose groups.

What can be inferred from the analysis information?

The registry lists 19 outcome measures and 0 analyses. It provides an endpoint population definition, but no primary endpoint estimates, group-level analysis counts, confidence intervals, or p-values. The listed enrollment does not substitute for a count of patients with evaluable concentration data. In general, an analysis population should be interpreted according to its defined eligibility and availability of measurements; here, the record says the pharmacokinetic set includes evaluable patients who received at least one dose between 0.125 mg and 0.5 mg, but does not give the resulting count.

The record does not report whether concentration values were transformed for analysis, how missing measurements were handled, or what model, if any, was used to compare groups. It does not identify covariates, prespecified contrasts, or estimation procedures beyond the geometric mean and geometric coefficient of variation. These details are not reported in the registry record and should not be inferred from the endpoint label.

How should uncertainty and planning illustrations be read?

In general, a confidence interval represents uncertainty around an estimated quantity under stated assumptions. Wider intervals indicate less precise estimation, while narrower intervals indicate greater precision within the model. No primary endpoint confidence interval is reported, so precision cannot be evaluated directly from this record. A p-value, if reported, would address compatibility with a specified null model; it would not by itself describe the size or clinical importance of a difference. The registry record reports no primary endpoint p-value.

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect; time-to-event illustrations are defined in terms of total events, while other illustrations are defined as participants per arm. Such planning quantities are hypothetical design calculations, not observed trial outcomes. They are not observed power and do not establish the design rationale for this study. The planning illustration is not a substitute for the absent endpoint estimates or their uncertainty.

In general, over-dispersion means the observed variation is greater than a model assumes. If present and ignored, it can make standard errors and inferential results unreliable. The registry record does not describe an over-dispersion assessment or a statistical model for the endpoint, so no claim about either can be made for this study.

What do the safety counts convey?

Adverse-event counts are descriptive summaries of affected patients in the listed groups. The serious-event counts are reported as 0 in each group, while other adverse-event affected counts are reported by dose group. These counts do not establish whether an event was caused by treatment, and they do not supply a comparative risk estimate. In general, safety interpretation also depends on the event definitions, observation period, completeness of reporting, and population at risk. The record provides some group-level counts but does not report further detail on those points. Death counts are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 19 outcome measures, including the primary pharmacokinetic endpoint and secondary outcomes related to drug-related adverse events, blood pressure, and pulse rate. It does not report an analysis plan describing how multiple outcomes or comparisons were handled. A multiplicity adjustment, testing hierarchy, or designation of confirmatory versus exploratory outcomes is not reported in the registry record.

In general, testing many outcomes or contrasts can increase the chance of at least one apparently unusual result if each is interpreted independently. Methods for handling this issue depend on the study objectives and planned analyses. Since the registry does not report those methods or the results, it is not possible to determine whether multiplicity was addressed, or how it might affect interpretation. No statistical significance claims can be assessed from the listed outcome count alone.

The pharmacokinetic analysis population is described as evaluable patients who received at least one dose between 0.125 mg and 0.5 mg. The number of patients meeting that definition, the number analyzed within each dose group, and the reasons for any exclusions are not reported in the registry record. The record does not describe missing concentration measurements, missing vital-sign data, imputation, or sensitivity analyses. These omissions prevent assessment of how incomplete data may have affected endpoint estimates.

In general, missing-data methods should be considered in light of why observations are absent and what assumptions an analysis makes about those absences. No such assumptions or methods are specified for this trial in the registry record. The listed enrollment should not be taken as the endpoint analysis count, and the safety counts should not be assumed to represent the same population used for the pharmacokinetic endpoint.

11. 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 5% reporting threshold.

Most frequent non-serious adverse event terms

The posted serious adverse-event figures list 0 affected patients in the 0.125 mg group, 0 in the 0.25 mg group, and 0 in the 0.5 mg group. The corresponding numbers at risk are 9, 15, and 2. These figures describe what is recorded in the registry; they do not establish that no serious events occurred outside the reported information or observation period. The death counts are not reported in the registry record.

For other adverse events, the affected counts are 2 among 9 at risk in the 0.125 mg group, 3 among 15 at risk in the 0.25 mg group, and 1 among 2 at risk in the 0.5 mg group. These are counts, not causal estimates or adjusted comparisons. The record does not provide event-level descriptions for these other events, nor does it report a statistical test comparing groups. The secondary outcome names include drug-related adverse events, but the listed group counts alone do not establish that each event was considered related to pramipexole.

In general, adverse-event counts are interpreted alongside event definitions, timing, duration of follow-up, and the method used to attribute relatedness. Details beyond the listed counts are not reported in the registry record. Given the non-randomized design and the different group sizes, the figures should be read descriptively rather than as evidence of a dose-related safety pattern.

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

This study addresses pharmacokinetics of pramipexole in pediatric patients with restless legs syndrome, using Cmax,ss as its primary endpoint. The registry describes the endpoint’s measurement and summary scale, and lists adverse-event counts by dose group. It does not report the primary concentration results, their variability, or statistical comparisons. Consequently, the posted information does not show the observed concentration profile or the precision of an estimate.

The record also does not provide symptom results that would quantify a clinical response to treatment. The primary endpoint is a plasma concentration measure, and the secondary outcomes listed concern adverse events and vital signs. No conclusion about symptom improvement can be drawn from the endpoint definition or safety counts.

The three dose groups were not randomized comparisons. Even if group results were available, differences would need to be interpreted with this design limitation in mind. The record does not describe an adjusted analysis that would address differences among the groups. It therefore cannot support a causal interpretation of dose-group contrasts.

The serious adverse-event counts are recorded as zero for each listed dose group, while other adverse-event counts are also reported. These figures are descriptive and do not establish comparative safety or causation. Death counts are not reported in the registry record. Further information about event details and the analysis of safety outcomes is not included.

In general, a study can inform a question only to the extent that its outcomes, analyses, and uncertainty are reported. Here, the registry identifies a pharmacokinetic question and a population definition, but does not provide the central endpoint estimates needed to judge the results. The appropriate interpretation is limited to the design and the recorded counts, rather than a conclusion about efficacy, dose response, or clinical benefit.

13. Why This Trial Matters Statistically

The statistical importance of this study lies in the distinction between describing drug exposure and estimating a treatment effect. Cmax,ss is a pharmacokinetic endpoint: it characterizes plasma concentration at steady state. It does not directly measure symptom change in restless legs syndrome. Keeping those estimands distinct prevents concentration summaries from being mistaken for evidence of clinical benefit.

The study also illustrates why design information is essential to interpreting group summaries. Non-randomized allocation and an open-label design do not ensure that the dose groups are comparable. Any between-group contrast would therefore require careful framing, and the registry record does not report a comparative analysis or adjustment method. The doses are useful descriptions of the groups studied, but do not make the groups a randomized dose-response experiment.

Reporting the analysis population is also important. The record defines the pharmacokinetic set in terms of evaluability and receipt of a dose in the stated range, but does not report how many participants met that definition or contributed to each estimate. Enrollment alone cannot communicate endpoint completeness or precision.

Finally, the record demonstrates the limits of interpreting safety counts without event-level detail, analysis methods, and complete reporting of related information. Counts can describe what was recorded, but cannot alone establish causation or a comparative pattern. For clinical researchers, these distinctions help separate the study’s stated question, design, available observations, and claims that the registry record does not support.

14. 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 most important limitation for interpreting results is that primary Cmax,ss estimates are not reported in the registry record. No dispersion estimate, confidence interval, p-value, or dose-group analysis is reported. The pharmacokinetic endpoint is therefore defined, but its observed values and precision cannot be evaluated from the posted results.

The design is non-randomized, open-label, and parallel. The registry itself indicates that the arms are not a like-for-like control comparison. The record does not describe how patients entered each dose group, what factors influenced dose optimization, or whether analyses adjusted for group differences. Any contrast between groups would consequently have limited causal interpretability.

Although enrollment is listed, the number of patients included in the pharmacokinetic analysis and the dose-specific analysis counts are not reported in the registry record. The record defines an evaluable pharmacokinetic population but does not report exclusions, missing concentration measurements, or the approach to missing data. It also does not explain the relationship between the brief summary’s single-dose description and the primary endpoint’s steady-state wording.

For safety, the record provides group-level serious and other adverse-event counts, but not event-level descriptions or a statistical comparison. Death counts are not reported in the registry record. The record lists vital-sign outcomes but does not provide their results. Methods for multiplicity, covariate adjustment, interim analyses, and endpoint analysis are not reported. These limitations constrain what can be concluded about pharmacokinetic differences, clinical effects, and comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Investigate Pharmacokinetics (PK) of Pramipexole in Pediatric Patients Who Are Individually Optimized to Stable Pramipexole Doses for the Treatment of Idiopathic Restless Legs Syndrome (RLS) — NCT02231918.
• Registry record last updated 2015-10-06; status last verified 2015-09.
• Results first posted 2015-10-06.
• 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.

18. Record Summary

NCT02231918 is a completed phase 2, open-label, non-randomized, parallel study sponsored by Boehringer Ingelheim. It examined pramipexole pharmacokinetics in pediatric patients with restless legs syndrome, with oral once-daily dose levels of 0.125 mg, 0.25 mg, and 0.5 mg. The registry lists enrollment of 26.

The primary endpoint was Cmax,ss, summarized as a geometric mean with geometric coefficient of variation. The record describes a pharmacokinetic analysis population and measurement times but does not report the primary endpoint estimates or statistical analyses. Secondary outcomes included drug-related adverse events, blood pressure, and pulse rate.

Serious adverse-event affected counts are listed as 0 in all three dose groups. Other adverse-event affected counts are listed as 2, 3, and 1 across the respective groups. Death counts and further statistical details are not reported in the registry record. The available information supports a description of the study design and recorded counts, not a conclusion about treatment effect or dose-group differences.