A Study in Healthy People to Compare Two Different Sifrol® Tablets: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study in Healthy People to Compare Two Different Sifrol® Tablets (NCT06457204), a randomized phase 1 study. The primary outcome is Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz).

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, open-label, single-dose, two-way crossover trial in healthy subjects. The crossover design means that subjects received both the reference tablet manufactured in Ingelheim and the test tablet manufactured in Ennigerloh. They were assigned to one of the two treatment orders: reference followed by test, or test followed by reference. The treatment periods were separated by a wash-out phase of at least 3 days.

Because each subject received both treatments, the comparison can account for stable differences between subjects by evaluating the treatment responses within the crossover structure. The order of treatments and the period in which a treatment is received still matter statistically, so the posted analysis included sequence, period, treatment, and subjects nested within sequence. The registry record does not report additional details of randomization procedures or concealment.

The trial was open-label, meaning that masking was not used. The primary outcome was a pharmacokinetic measure of pramipexole exposure, rather than a clinical symptom or disease outcome. The record lists enrollment as 28 and status as completed. It gives a start date of 2024-07-02 and a primary completion date of 2024-08-12. The sponsor was Boehringer Ingelheim.

The registry record describes the objective as establishing bioequivalence between tablets manufactured at two sites. It does not report the protocol's planned bioequivalence margins, the planned sample-size justification, or whether any interim analyses were conducted. Those omissions limit what can be concluded about the trial's design criteria and decision process from the registry information alone.

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: All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated

Period 1

Washout

Reasons for not completing this period:

Period 2

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic set (PKS): all subjects in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK nonevaluability.

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: Treated set (TS): All subjects who were treated with at least one dose of trial drug.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz), measured over Within 3 hours prior to drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 34 and 48 hours following administration..

The primary endpoint was the area under the plasma concentration-time curve of pramipexole from 0 to the last quantifiable data point, called AUC0-tz. The reported unit is hour * picogram per milliliter. This measure represents accumulated drug concentration in plasma across the defined observation period. The record specifies blood sampling within 3 hours prior to administration and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 34 and 48 hours following administration.

For a comparison of formulations, pharmacokinetic exposure is useful because it describes how much drug is present in the circulation over time. AUC0-tz focuses on the observed concentration-time profile up to its last quantifiable point. The registry record also lists AUC0-∞ as a secondary outcome, which extends the exposure measure to infinity by estimation; its result is not included in the posted details summarized in the record.

The primary endpoint was analyzed on a logarithmic scale, then the estimates and confidence interval were transformed back to the original scale. This is a common approach for pharmacokinetic exposure measures, which are often analyzed using multiplicative comparisons. The posted primary comparison is expressed as a ratio of adjusted geometric means. AUC0-tz is an exposure endpoint, not a direct measure of how a treatment affects symptoms, function, or a health outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint description says that AUC0-tz was analyzed using analysis of variance on the logarithmic scale. The model included sequence, subjects nested within sequences, period, and treatment. Subjects nested within sequences were treated as a random effect; the other listed effects were treated as fixed effects. Confidence intervals were calculated from the residual error of the analysis of variance and quantiles from the t-distribution. Estimates and confidence limits were then back-transformed to the original scale.

Why analyze the endpoint on a logarithmic scale?

In general, pharmacokinetic exposure values are often better represented by multiplicative relationships than by additive differences. A logarithmic transformation converts multiplicative comparisons into additive contrasts for model fitting. When those contrasts are transformed back, the results can be expressed as ratios on the original scale. This explains why the registry record reports a ratio of adjusted geometric means rather than an arithmetic difference between treatment means.

The reported arm values are geometric least squares means. These are model-based summaries on the original scale after analysis on the logarithmic scale. They are not ordinary arithmetic averages. The ratio of adjusted geometric means is the principal comparison reported for the primary endpoint; its 90% confidence interval communicates the uncertainty of that comparison under the fitted model.

What does the crossover model contribute?

In general, crossover trials compare treatments within subjects, because each subject receives the treatments in different periods. This can reduce the influence of stable between-subject variability on the treatment comparison. It also requires consideration of sequence and period: sequence represents the order in which treatments are received, and period represents when a treatment is administered within the crossover. The model described in the record includes both effects, along with treatment and subjects nested within sequence.

The record classifies subjects nested within sequences as random and the other listed model effects as fixed. In general, a random effect represents variation across a sampled set of subjects or clusters, while fixed effects estimate specific contrasts among the modeled categories. The registry description does not give further details about model diagnostics, assumptions checks, or how any departures from those assumptions were handled.

How should the confidence interval be read?

The reported 90% confidence interval runs from 98.4% to 105.0% for the ratio of adjusted geometric means. In general, a confidence interval is a range of estimates compatible with the observed data and the analysis procedure at its stated confidence level. It is not a guarantee that the true value lies within the interval, and it does not indicate the probability that a particular value is true. Its interpretation also depends on the model and the sampling assumptions.

The registry record says that the interval was based on residual error from the analysis of variance and quantiles from the t-distribution, followed by back-transformation. The record does not report the numerical residual error, degrees of freedom, or a p-value for this comparison. Those quantities should not be inferred from the reported interval.

What role do planning illustrations have?

Any sample-size planning illustration based on the observed effect is a forward-looking calculation under stated assumptions, not a description of the trial's actual enrollment decision and not observed power. The assumptions described for such an illustration are a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation, with the effect to detect defined as a stated fraction of the observed effect. The record does not report the trial's own sample-size justification. A planning calculation cannot replace that missing design rationale or establish how likely the completed trial was to detect an effect.

In general, the assumptions used for a planning exercise matter: a different target effect or analysis approach can yield a different planning requirement. The registry record's planning assumptions are not evidence that the trial was designed around any particular fraction of the observed effect. Nor should an illustrative planning result be interpreted as an observed clinical or pharmacokinetic outcome.

What is not described about the analysis?

The registry record does not report a full statistical analysis plan, detailed handling of missing concentration measurements, sensitivity analyses, model diagnostics, or a multiplicity adjustment. It also does not report the bioequivalence margins needed to compare the confidence interval with a decision criterion. Those omissions mean the posted analysis can be described, but some design and inferential choices cannot be independently assessed from the registry record alone.

10. Analyses Reported by the Sponsor

The registry record reports a sponsor analysis for the primary comparison: the ratio of adjusted geometric means is 101.6%, with a 90% confidence interval from 98.4% to 105.0%. The endpoint description identifies the analysis of variance on the logarithmic scale, the model effects, and the back-transformation used to express estimates on the original scale. This reported comparison is the relevant posted result for interpreting the primary endpoint.

The record also lists arm-specific geometric least squares means of 3573.0 for the reference product and 3632.0 for the test product, with their respective pharmacokinetic analysis counts. These summaries do not include a separately reported recalculated comparison estimate in the registry record. A direct calculation from arm summaries would not reproduce all features of the crossover model, including its adjustment for sequence, period, and subjects within sequences. The sponsor's reported ratio and interval should therefore be distinguished from any simple unadjusted recalculation.

The registry record does not flag a discrepancy between the reported analysis and a recalculated result. It does not report a p-value for the primary comparison. Since the bioequivalence acceptance limits are also not reported in the registry record, the sponsor's numerical result can be described precisely, but the decision criterion cannot be independently checked from the record.

11. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is AUC0-tz. The registry record lists three outcome measures and three analyses, and identifies AUC0-∞ as a secondary outcome. It does not give complete posted results for every listed outcome and analysis. Multiplicity concerns arise when several outcomes or comparisons are examined: in general, the more inferences considered, the more important it is to understand whether and how the analysis controlled the chance of false-positive findings across them.

A multiplicity adjustment or strategy is not reported in the registry record. It is also not clear from the record whether the primary endpoint was the only confirmatory test or how secondary endpoints were intended to contribute to conclusions. The primary comparison should therefore be interpreted as the result reported for that endpoint, without assuming a broader multiplicity plan.

The primary endpoint population is the pharmacokinetic set. It includes subjects in the trial set who provided at least one primary or secondary pharmacokinetic endpoint and were not excluded because of a protocol deviation relevant to pharmacokinetic evaluation or pharmacokinetic nonevaluability. The registry record does not provide a full participant flow or explain all exclusions and missing observations in detail. Specific methods for handling missing concentration measurements are not reported in the registry record.

The pharmacokinetic counts listed with the primary outcome are 26 for the reference product and 27 for the test product. The adverse-event at-risk counts are 26 and 28, respectively. Since these counts refer to different reported analyses and populations, they should not be combined or assumed to describe the same set of evaluable observations. The record does not report a sensitivity analysis comparing alternative analysis populations or missing-data assumptions.

In general, missingness can affect a pharmacokinetic estimate if the unavailable measurements are related to exposure or to the probability of being evaluable. Without detail on the pattern and handling of missing data, the extent of any such influence cannot be assessed from the registry record. The same caution applies to exclusions due to protocol deviations: the record defines their relevance in broad terms but does not enumerate them.

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 non-serious adverse event terms

The registry record reports no serious adverse events in either treatment group: 0 among 26 at risk for the reference product, and 0 among 28 at risk for the test product. It reports no deaths in either group. The record does not list serious adverse-event terms.

Other adverse events are reported for 7 among 26 at risk in the reference group and 5 among 28 at risk in the test group. These are posted counts, not a statistical comparison. The record does not provide a detailed breakdown of the other adverse events in the information, so their nature, severity, timing, and relationship to treatment cannot be described further.

These safety counts should be read in light of the trial's design: subjects received both treatments in different periods. The registry record lists at-risk counts by treatment but does not explain whether or how events occurring across periods were attributed for these summaries. No conclusion about comparative safety should be drawn from the counts alone. The information concerns this completed single-dose trial in healthy subjects and does not describe longer-term safety.

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

The result describes a comparison of pramipexole exposure after one oral dose of two Sifrol® tablets made at different manufacturing sites. The reported primary estimate is a ratio of adjusted geometric means of 101.6%, and its 90% confidence interval extends from 98.4% to 105.0%. These figures summarize the model-based comparison for AUC0-tz in the pharmacokinetic set.

The registry record states that the objective was to establish bioequivalence. However, an objective is not itself a conclusion. To assess whether a bioequivalence criterion was met, the interval must be interpreted against the prespecified acceptance limits and analysis rules. Those limits are not reported in the registry record. The estimate and interval therefore communicate the posted statistical result, but they do not allow an independent verification of a formal bioequivalence decision.

The endpoint measures drug exposure in plasma over a defined sampling period. It does not measure symptom improvement, disease control, quality of life, or long-term outcomes. The trial enrolled healthy subjects and used a single-dose design, so its endpoint and population should not be treated as direct evidence about clinical outcomes in patients or use over time. The registry record also does not report evidence about comparative effectiveness.

The confidence interval conveys precision for the estimated ratio under the stated analysis. It is not a range of individual subject responses, and it does not resolve questions the trial did not measure. In general, statistical compatibility with a range of values should not be confused with proof of identity or with a clinical recommendation.

The posted adverse-event information is limited to the counts of serious and other adverse events and deaths. It does not provide enough detail to characterize event types or draw a broad comparative safety conclusion. Overall, the result is best understood as a model-based pharmacokinetic comparison under the specific crossover conditions recorded, with important decision criteria and additional analysis details not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates how a crossover design can be used to compare pharmacokinetic exposure between two formulations while accounting for the fact that the same subjects receive both treatments. The treatment-order sequences, periods, treatment effect, and subjects nested within sequences are all represented in the primary analysis description. This structure is relevant because a crossover comparison is not the same as a comparison of independent groups.

The endpoint also demonstrates why the scale of analysis matters. AUC0-tz was analyzed after logarithmic transformation, and the reported result was back-transformed into a ratio of adjusted geometric means. Readers can distinguish that model-based ratio from the arm-specific geometric least squares means and avoid treating the latter as an independent-groups estimate.

The interval is central to interpretation. The point estimate alone does not show how precisely the comparison was estimated; the 90% confidence interval gives a range of values compatible with the analysis. But precision and a formal bioequivalence decision are not interchangeable. Without the acceptance margins, a reader cannot independently determine whether the registry's stated objective was achieved according to the planned criterion.

The registry record also provides a useful reminder to keep analysis populations and safety counts separate. The pharmacokinetic counts differ from the adverse-event at-risk counts, reflecting different reported summaries. Treating those counts as if they described one identical analytic set would obscure the distinction between outcome-specific populations.

Finally, the available information supports a focused interpretation: exposure after a single dose in healthy subjects, analyzed through the stated crossover model. The missing design and analysis details—including the sample-size justification, multiplicity approach, and bioequivalence limits—bound what can be independently evaluated. Recognizing those boundaries is part of sound statistical interpretation.

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 registry record does not report the bioequivalence acceptance limits. This is a central limitation for evaluating the stated objective: the ratio and confidence interval can be described, but cannot be compared against the decision boundaries from the registry information alone.

The record describes the primary model but does not report a full statistical analysis plan, model diagnostics, or sensitivity analyses. It does not describe in detail how missing pharmacokinetic observations were handled, how many observations were missing, or the reasons for pharmacokinetic nonevaluability. The pharmacokinetic set is defined, but a full account of exclusions and participant flow is not reported in the registry record.

Three outcome measures and three analyses are listed, but multiplicity handling is not reported. The record does not give complete results for all listed outcomes and analyses in the details available. It also does not report the trial's sample-size justification or whether interim analyses were planned or conducted. The planning assumptions described for illustrative sample-size calculations should not be taken as the trial's own design rationale.

The reported arm-specific endpoint values do not include dispersion estimates in the record, while the comparison ratio and confidence interval are reported separately. The record does not provide a p-value for the primary comparison. These omissions limit the range of independent checks that can be made from the posted information.

Generalisability is also limited by the recorded setting: a single-dose crossover trial in healthy subjects comparing two manufacturing-site versions of the same named tablet. The primary endpoint is plasma exposure, not a clinical outcome, and the safety information is limited to adverse-event counts. Further details about demographics, event descriptions, and longer-term observation are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study in Healthy People to Compare Two Different Sifrol® Tablets — NCT06457204.
• Registry record last updated 2025-08-28; status last verified 2025-08.
• Results first posted 2025-08-28.
• 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

NCT06457204 is a completed Phase 1, randomized, open-label, single-dose, two-way crossover trial sponsored by Boehringer Ingelheim. It enrolled healthy subjects and compared Sifrol® tablets containing 0.088 mg pramipexole manufactured in Ingelheim and Ennigerloh. The registry record lists a start date of 2024-07-02 and a primary completion date of 2024-08-12.

The primary endpoint was AUC0-tz, analyzed in the pharmacokinetic set using analysis of variance on the logarithmic scale. The reported ratio of adjusted geometric means is 101.6%, with a 90% confidence interval from 98.4% to 105.0%. Bioequivalence limits are not reported in the registry record, so the formal criterion cannot be checked from the posted information.

The registry record reports 0 serious adverse events in each treatment group and no deaths. Other adverse events were reported for 7 among 26 at risk for the reference product and 5 among 28 at risk for the test product.