Bioequivalence of Pramipexole Extended Release (PPX ER) 1.5mg x 1 Tablet Once Daily (q.d.) vs. PPX ER 0.375mg x 4 Tablets Under Fasted and Fed Conditions in Japanese Healthy Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bioequivalence of Pramipexole Extended Release (PPX ER) 1.5mg x 1 Tablet Once Daily (q.d.) vs. PPX ER 0.375mg x 4 Tablets Under Fasted and Fed Conditions in Japanese Healthy Volunteers (NCT01119443), a randomized phase 1 study. The primary outcome is AUCτ,ss (Fed Conditions).

2. Clinical Question

The study addressed whether exposure to pramipexole extended-release at steady state differed between two ways of taking the same stated daily dose: one 1.5 mg tablet once daily and four 0.375 mg tablets once daily. The primary endpoint focused on the comparison under fed conditions. The registry summary also identifies a food-effect question for the 1.5 mg tablet, and the treatment sequences included both fed and fasted administration.

This is a pharmacokinetic comparison rather than a comparison of clinical outcomes. The primary endpoint was area under the plasma concentration-time curve over a dosing interval at steady state. The record reports an analysis for the fed-condition comparison, but does not report a primary endpoint result for the fasted comparison in the posted primary outcome. Although the record names food effect as an objective, a specific food-effect estimate is not reported in the registry record.

3. Trial Design

This was a Phase 1, randomized, open-label, crossover study sponsored by Boehringer Ingelheim. The registry records an enrollment of 28 and describes the participants as healthy Japanese male volunteers. The study started in 2010-04, reached primary completion in 2010-06, and is marked completed.

A crossover design exposes participants to more than one treatment condition in a sequence, so comparisons can be made within participants rather than only between separate groups. Here, treatment sequence A and treatment sequence B list the two tablet regimens under fed and fasted conditions in differing orders. The official title describes multiple dosing with increasing dose and a two-way crossover comparison. The precise period durations, washout arrangements, and rules for moving between conditions are not reported in the registry record.

The study was unmasked, meaning the registry records no masking. The listed regimens were pramipexole extended-release 1.5 mg as one tablet once daily and 0.375 mg as four tablets once daily. Both formulations are identified as drug interventions. The primary pharmacokinetic data set excluded one subject who discontinued on Day 1 of Visit 4, leaving 27 participants in each of the two reported fed-condition groups.

The primary outcome was AUC at steady state under fed conditions, measured from serial pharmacokinetic blood samples. The registry lists 16 outcome measures and 14 analyses, while 12 secondary outcomes are posted. Secondary measures include trough and minimum concentrations, time to maximum concentration, elimination and half-life measures, and mean residence time, with several specified for fed or fasted conditions. Results for outcomes without an estimable two-arm comparison are not included in the reported comparison. The randomization method and allocation concealment procedures are not reported in the registry 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.

Up-titration Period (10 Days)

Crossover Period 1 (5 Days)

Reasons for not completing this period:

Crossover Period 2 (5 Days)

Crossover Period 3 (5 Days)

Analysis population for the primary outcome, as defined in the registry: One subject who discontinued the study on Day 1 of Visit 4 (the first day of the first crossover period) was excluded from Pharmacokinetic data set

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 AUCτ,ss (Fed Conditions), measured over Serial pharmacokinetic blood samples collected before drug administration, 1, 2, 2.5, 3, 4, 6, 8, 10, 12, and 23.833 hours after drug administration.

The primary endpoint, AUCτ,ss under fed conditions, measures the area under the plasma concentration-time curve for the analyte over one uniform dosing interval at steady state. The registry describes serial blood sampling before administration and at 1, 2, 2.5, 3, 4, 6, 8, 10, 12, and 23.833 hours after administration. AUC combines concentration information across the dosing interval rather than relying on a single blood concentration. The subscripted notation identifies the dosing interval and steady-state assessment.

In general, pharmacokinetic AUC is used to characterize overall drug exposure over a specified interval. For a bioequivalence question, comparing exposure from alternative formulations can help assess whether the formulations produce similar concentration-time exposure under the stated study conditions. This is a pharmacokinetic purpose; it is not itself a direct measure of symptoms, function, or other clinical benefit.

The registry reports geometric means for the two fed regimens. The one-tablet 1.5 mg regimen had a geometric mean of 33.7 ng·h/mL, with a standard deviation of 5.89; the four-tablet 0.375 mg regimen had a geometric mean of 32.3 ng·h/mL, also with a standard deviation of 5.89. Each reported group included 27 participants. The record gives the endpoint's dispersion as standard deviation. It does not report the individual concentration profiles or the raw participant-level AUC values, so the endpoint's distribution cannot be inspected from the registry summary alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The sponsor's reported analysis is an ANOVA comparison expressed as a test/reference ratio of the mean multiplied by 100. It reports a value of 104.2 and a 90% confidence interval from 98.3 to 110.3. The reported arm summaries are geometric means, which are commonly used for pharmacokinetic measures when values are positively skewed or naturally interpreted on a multiplicative scale. The registry does not give the full ANOVA model specification, transformation details, or the precise definition of the test and reference labels.

What does a crossover design contribute?

In general, a crossover study assigns participants to sequences that expose them to more than one treatment. Each participant can then contribute observations under different conditions. This can be statistically efficient because a participant can act as their own comparison, helping account for stable characteristics that otherwise contribute to between-person variability. This advantage depends on adequate conduct of the sequences and an analysis that accounts for the structure of the repeated observations.

The registry identifies the study as randomized and crossover, and lists two treatment sequences. It does not report how the random sequence was generated, how allocation was concealed, the length of each treatment period, or the washout procedures. The posted summary also does not describe whether period or sequence effects were included in the ANOVA. Those omissions limit independent assessment of the crossover analysis. A crossover design does not automatically remove all sources of bias or variability; changes over time, treatment-period effects, or residual effects from an earlier treatment may matter in general.

What does the ratio express?

In general, a ratio compares one estimate with another on a relative scale. A ratio expressed as a percentage uses 100 as the equal-estimate reference point. The sponsor's value of 104.2 is presented as the test/reference ratio multiplied by 100. The registry does not specify in the reported analysis which named regimen is assigned to each role, so the direction should be retained using the sponsor's test/reference terminology rather than inferred. The ratio is not a percentage of participants and is not an absolute concentration or exposure measurement.

A geometric mean summarizes data using a multiplicative scale. In general, it is useful when relative changes are more interpretable than additive changes, as often occurs with pharmacokinetic measurements. The standard deviations of 5.89 accompany the arm-level geometric means in the registry record. They should not be confused with the 90% confidence interval for the ratio: the former describe dispersion for the individual arm summaries as reported, while the latter represents uncertainty around the comparison estimate.

How should the confidence interval be read?

In general, a confidence interval is an uncertainty range generated by a specified statistical procedure. A 90% confidence interval does not mean that 90% of participants' values fall inside its endpoints. Nor does it indicate the probability that a particular fixed treatment effect lies inside this one interval. It describes the performance of the interval-generating method over repeated studies under its assumptions.

For formal equivalence assessment, an interval is interpreted against prespecified lower and upper acceptance limits. Those limits determine what differences are considered sufficiently small for the stated purpose. They are not reported in the registry record. The interval from 98.3 to 110.3 includes 100, but that fact alone is not enough to conclude equivalence: an interval may include 100 and still extend beyond an applicable acceptance boundary. The registry's classification of the analysis as non-inferiority or equivalence identifies the analysis type, but it does not supply the missing decision criteria.

Why can over-dispersion matter?

In general, over-dispersion means that the observed variability is greater than a model's assumptions allow. If a model understates variability, its standard errors and confidence intervals can be too small, making estimates appear more precise than warranted. If variability is modeled too conservatively, uncertainty may be overstated. This is a general statistical consideration, not a finding that over-dispersion occurred in this study. The registry record does not report a diagnostic assessment of model fit or over-dispersion.

What is the role of planning calculations?

In general, sample-size illustrations based on an observed effect are planning exercises, not observed power. They can show what sample size might be needed under specified assumptions, but do not establish the probability that a completed trial detected an effect. Any such interpretation depends on assumptions about the target effect, variability, significance level, allocation, and analysis. The registry record does not report the original sample-size justification or the assumptions behind the study's enrollment target. No inference about the trial's original power calculation can be made from the reported enrollment alone.

The reported primary endpoint comparison used 27 participants in each fed-condition group. The record states that one participant who discontinued on Day 1 of Visit 4 was excluded from the pharmacokinetic data set. The consequences of this exclusion for the estimate cannot be quantified from the summary. General methods for missing-data sensitivity analysis would require further information about the missing observations and the analysis population, neither of which is detailed in the registry record.

10. Analyses Reported by the Sponsor

The registry reports the sponsor's ANOVA result as a test/reference ratio of 104.2, with a 90% confidence interval from 98.3 to 110.3. This is the available inferential comparison for the primary endpoint under fed conditions. The arm-level summaries are geometric means of 33.7 ng·h/mL and 32.3 ng·h/mL, with a standard deviation of 5.89 in each group and 27 participants in each group.

A separate unadjusted recalculated ratio is not reported in the registry record, so a numerical agreement check between the sponsor analysis and a recalculation cannot be made from the registry summary. The arm-level summaries are not a substitute for the sponsor's ANOVA: the ANOVA may reflect the crossover structure, while simple calculations from group summaries do not necessarily preserve paired information or model adjustments. No discrepancy is flagged in the registry record. The sponsor's reported analysis is therefore the estimate to use when describing the posted inferential result, while recognizing that the interval and its formal interpretation depend on criteria not reported in the record.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures, 14 analyses, and 12 posted secondary outcomes. The primary endpoint is AUCτ,ss under fed conditions. Secondary outcomes include pharmacokinetic measures such as Cτ,ss, Cmin,ss, Tmax,ss, λz,ss, t1/2,ss, and MRTpo,ss, with several measures specified for fed or fasted conditions. The record does not report a multiplicity adjustment or explain how the primary and secondary analyses were prioritized when interpreting results.

Multiplicity is a general concern when multiple outcomes or comparisons are tested: the chance of at least one apparently unusual result can increase as the number of tests increases. Methods such as adjusting significance thresholds or defining a hierarchical testing plan can address this, but the method depends on the analysis plan. Such a plan is not reported in the registry record. The primary analysis is presented with a confidence interval and no p-value; the registry's reported p-value is not available. The listed 14 analyses should not be treated as a complete testing strategy without further details.

For the primary pharmacokinetic data set, one subject who discontinued on Day 1 of Visit 4 was excluded. The record does not state whether the participant contributed any usable pharmacokinetic observations before discontinuation, whether missing values were imputed, or whether sensitivity analyses were performed. It identifies 27 participants in each fed-condition comparison group. The basis for the secondary-outcome analysis populations is not described in the posted record.

In general, analysis populations can differ, for example by including all randomized participants or only those with evaluable measurements. The registry identifies an exclusion for the pharmacokinetic data set but does not provide a full set of population definitions. It also does not report a detailed missing-data strategy, protocol deviations, or the number of participants contributing to each secondary analysis. These gaps make it difficult to assess how missing observations or multiple testing may affect interpretation beyond the reported primary comparison.

12. 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 registry reports serious adverse events affecting 0 of 28 participants during up-titration, 0 of 28 during the 1.5 mg once-daily fed condition, and 0 of 27 during the 1.5 mg once-daily fasted condition. These are the serious-event counts and numbers at risk for the listed groups. The record does not list serious adverse-event terms. Death counts are not reported in the registry record; a blank or unavailable death count should not be read as a reported zero.

The registry separately reports other adverse events affecting 5 of 28 participants during up-titration, 5 of 28 during the fed condition, and 0 of 27 during the fasted condition. No event terms are specified in the listed summary. The group descriptions relate to study conditions or periods, and the record does not establish whether the same participants contributed events in more than one group. The counts should not be added to obtain a total number of unique participants.

In general, a zero count in a small study means that no event was recorded in the specified group during the reported observation; it does not establish that the event cannot occur. Safety counts from this Phase 1 study describe the registry's reported observations and do not by themselves characterize uncommon or longer-term risks. The record does not provide additional event detail or follow-up information needed for broader safety conclusions.

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

The posted result describes a steady-state pharmacokinetic comparison under fed conditions between one 1.5 mg pramipexole extended-release tablet once daily and four 0.375 mg tablets once daily. The sponsor reported a test/reference ratio of 104.2 and a 90% confidence interval from 98.3 to 110.3. The arm-level geometric means were 33.7 ng·h/mL and 32.3 ng·h/mL, with 27 participants in each group. These results characterize the reported AUC comparison in the analyzed participants.

The result does not, by itself, establish formal bioequivalence. Formal interpretation requires knowing the acceptance boundaries and analysis rules, which are not reported in the registry record. Although the interval includes 100, its relation to any prespecified equivalence limits cannot be assessed from the posted information. The record's label of the analysis as non-inferiority or equivalence does not replace those criteria.

The primary result also does not establish that the two regimens are identical, or that all pharmacokinetic measures are alike. It pertains to AUC at steady state under fed conditions, not necessarily to the fasted condition or to every secondary measure. A distinct estimate of the food effect for the 1.5 mg regimen is not reported in the registry record. Nor does AUC alone establish differences or similarities in clinical outcomes.

The study enrolled healthy Japanese male volunteers and was conducted as a randomized, open-label crossover trial. Results in this study population and under these conditions should not be assumed to describe other populations or settings. The primary pharmacokinetic data set excluded one participant after discontinuation on Day 1 of Visit 4. The available record does not provide participant-level data, a complete missing-data analysis, or the details of the crossover model, so the influence of these factors cannot be independently evaluated from the registry summary.

In general, a registry result is most informative when read with its endpoint definition, analysis method, uncertainty interval, study population, and limitations. Here, those details support a narrow interpretation of the fed-condition AUC estimate, while leaving important elements of formal equivalence assessment unreported. Nothing in this result is a medical recommendation.

14. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates a formulation comparison in a crossover setting. The target is relative pharmacokinetic exposure for two tablet configurations, not a difference in a patient-centered outcome. Reporting the estimate as a test/reference ratio makes the comparison interpretable on a relative scale, while the confidence interval communicates uncertainty around that estimate.

The registry also highlights the importance of separating descriptive summaries from the inferential analysis. The geometric means and standard deviations describe the two reported fed-condition groups. The ANOVA ratio and its confidence interval represent the sponsor's model-based comparison. Because the study is a crossover, an analysis that accounts for within-participant observations may not be reproducible from arm-level summaries alone. The record does not include enough model detail to independently reconstruct that analysis.

Another statistical lesson is that an interval around a ratio cannot be interpreted in isolation when the question is equivalence. A formal conclusion depends on acceptance limits and a stated decision procedure. Neither is reported in the registry record. The result therefore provides an estimate with uncertainty, but not all information needed to evaluate the formal bioequivalence decision.

The study's population and endpoint also define its scope. The result concerns healthy Japanese male volunteers and steady-state AUC under fed conditions. It does not settle the fasted-condition comparison, provide a complete account of the food effect, or answer clinical outcome questions. The registry's listed secondary measures show that pharmacokinetic assessment extended beyond AUC, but not all of those outcome results are available in the posted summary.

Finally, the exclusion of one participant and the limited safety counts illustrate why analysis populations and missing-data handling matter even in a small pharmacokinetic study. The record gives the reason and timing of the exclusion, but not a complete sensitivity assessment. Interpreting the reported estimate alongside those limits keeps the statistical conclusion aligned with the evidence actually recorded.

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 summary does not report the equivalence acceptance limits or a full prespecified statistical analysis plan. This is a material limitation for interpreting an analysis classified as non-inferiority or equivalence. The reported confidence interval can be described, but the formal decision rule cannot be checked without the relevant margins and planned testing approach.

The primary outcome is reported for the fed condition only. Although the trial sequences include fasted administration and the registry summary identifies a food-effect objective, a separate fasted-condition primary comparison and a specific food-effect estimate are not reported in the registry record. The posted secondary outcome list includes pharmacokinetic measures, but does not supply all outcome results or the number analyzed for every measure.

One subject who discontinued on Day 1 of Visit 4 was excluded from the pharmacokinetic data set. The record does not provide more information about missing observations, reasons beyond the stated discontinuation, or sensitivity analyses. It also does not detail the crossover model, treatment-period durations, washout, or assessment of period and sequence effects. These gaps restrict independent evaluation of the statistical analysis and the possible influence of the exclusion.

The study was open-label and included healthy Japanese male volunteers. The record does not describe masking, and the findings are limited to the enrolled population and study conditions. The sample was 27 participants per reported fed regimen in the pharmacokinetic comparison. The registry does not report the original sample-size justification, so enrollment cannot be interpreted as evidence of a particular power target.

Safety reporting is also limited: the listed summary gives counts of participants affected, but no serious-event terms, and death counts are not reported in the registry record. The other adverse-event terms and detailed follow-up are not included. Together, these omissions mean the record supports a focused description of the reported fed-condition AUC result, rather than a complete independent appraisal of the protocol, all outcomes, or safety profile.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Bioequivalence of Pramipexole Extended Release (PPX ER) 1.5mg x 1 Tablet Once Daily (q.d.) vs. PPX ER 0.375mg x 4 Tablets Under Fasted and Fed Conditions in Japanese Healthy Volunteers — NCT01119443.
• Registry record last updated 2014-06-09; status last verified 2014-05.
• Results first posted 2011-06-27.
• 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

NCT01119443 is a completed Phase 1 randomized, open-label crossover study sponsored by Boehringer Ingelheim. It enrolled 28 healthy Japanese male volunteers and compared pramipexole extended-release 1.5 mg as one once-daily tablet with 0.375 mg as four once-daily tablets under fed and fasted conditions. The primary endpoint was steady-state AUC over a dosing interval under fed conditions.

The registry reports 27 participants per fed regimen in the primary pharmacokinetic data set after one subject discontinued on Day 1 of Visit 4 and was excluded. The sponsor's ANOVA result is a test/reference ratio of 104.2, with a 90% confidence interval from 98.3 to 110.3. Formal equivalence limits, complete model details, and a specific food-effect estimate are not reported in the registry record. Serious adverse events affected 0 participants in each listed group; death counts are not reported.