Effect of BIA 9-1067 on the Pharmacokinetics and Pharmacodynamics of Warfarin: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of BIA 9-1067 on the Pharmacokinetics and Pharmacodynamics of Warfarin (NCT02169440), a randomized phase 1 study. The primary outcome is Cmax - Maximum Observed Plasma Concentration (BIA 9-1067 + Warfarin).

2. Clinical Question

3. Trial Design

This was a phase one, randomized, unmasked crossover study, with a recorded enrollment of 20. It is marked completed. The recorded study start is 2009-06 and the primary completion is 2009-07. The sponsor is Bial - Portela C S.A. The record title describes the investigation as involving healthy volunteers, while its conditions listing names Parkinson's Disease (PD); no explanation resolving that difference is reported in the registry record.

The two sequences differed in the order of treatment. Group 1 received BIA 9-1067 plus warfarin in Period 1 and warfarin in Period 2. Group 2 received warfarin in Period 1 and the combination in Period 2. In a crossover design, participants receive the conditions in a sequence, allowing measurements under different conditions to be obtained from the same participant. This design can make within-participant comparisons useful, but interpretation depends on details such as period timing, treatment duration, and any measures used to address carryover. Those details are not reported in the registry record.

Randomization identifies the study as randomized, but the method used to generate or conceal the sequence is not reported in the registry record. Masking is listed as none. The record does not describe the reasons for choosing this design, the sample-size justification, or any planned interim analyses. It lists nine outcome measures, but no statistical analysis records. The primary completion date marks completion of primary data collection as recorded; it does not by itself indicate that results were posted or that a particular analysis was performed.

The posted primary outcome is a continuous pharmacokinetic measure: mean Cmax for BIA 9-1067 following co-administration with warfarin. Its collection timeframe includes a pre-dose measurement and post-dose measurements through 144 h. The record also describes the broader aim in terms of S-warfarin pharmacokinetics. The distinction between that stated aim and the named primary measure is important when interpreting what the recorded endpoint can establish.

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.

Overall Study

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 Cmax - Maximum Observed Plasma Concentration (BIA 9-1067 + Warfarin), measured over before dose and ½, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h post- dose..

Cmax is the maximum observed plasma concentration of a drug after administration. It is a pharmacokinetic measure: it describes the highest concentration observed in the sampled concentration-time profile, rather than a clinical symptom, diagnosis, or long-term outcome. The primary outcome is specified as the mean Cmax of BIA 9-1067, in ng/mL, after an oral single dose of 25 mg warfarin co-administered with 25 mg BIA 9-1067. The listed sampling schedule runs from before dosing through 144 h after dosing.

In general, Cmax is used to characterize the peak concentration reached under a dosing condition. Comparing concentration profiles can help describe how co-administration is associated with pharmacokinetic behavior. The posted outcome title identifies the combination condition; the record does not provide numerical values for the mean or standard deviation, or a corresponding warfarin-alone Cmax for BIA 9-1067. It therefore does not support a quantitative comparison of peak concentrations between the treatment conditions.

The study's brief summary frames its purpose as assessing the effect of BIA 9-1067 on the pharmacokinetics of S-warfarin, with CYP2C9 inhibition as the subject of interest. The listed primary measure, however, is BIA 9-1067 Cmax with warfarin. These are not interchangeable endpoints. The registry record does not report numerical primary-outcome results or an analysis linking the listed measure to a change in S-warfarin pharmacokinetics.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a randomized crossover design and a continuous primary outcome reported as a mean with standard deviation. It does not report the statistical methods used to analyze the primary outcome. The explanations below describe general statistical concepts relevant to this design; they do not assert that the study used a particular model or analysis procedure.

What does a crossover design compare?

In general, a crossover study assigns participants to treatment sequences so that each participant receives more than one condition at different periods. The two sequences in this record reverse the order of warfarin alone and BIA 9-1067 with warfarin. Because measurements can be made under both conditions in the same participant, a within-participant contrast can account for stable differences between participants. This can be useful when the outcome varies considerably from person to person.

A crossover comparison also requires attention to features that are specific to time and sequence. Period effects occur when measurements differ across periods for reasons other than treatment. Carryover refers to an effect of an earlier treatment persisting into a later period. Randomization of sequence can help balance some sources of bias, but does not remove the need to consider these issues. The registry record does not report the period interval, any washout procedure, checks for carryover, or an analysis of period or sequence effects. It is not possible to determine from the record how these design features were handled.

What does the listed mean and standard deviation describe?

In general, a mean is a measure of the center of a set of observations, and a standard deviation describes how spread out individual observations are around that mean. The primary outcome entry specifies mean and standard deviation as the summary form. These summaries would describe the distribution of Cmax measurements for the specified condition, but a treatment comparison would also require results for the comparator condition and a defined contrast. Neither the numerical summaries nor a contrast are reported in the registry record.

The maximum observed concentration is drawn from a series of measurements over time. Its value can depend on the timing of observations as well as the concentration profile. The listed schedule includes measurements before dosing and at multiple post-dose times through 144 h. The record does not report individual concentration-time data, participant-level Cmax values, or the method used to handle observations that might be unavailable or occur between scheduled collection times.

What would an uncertainty estimate add?

In general, a confidence interval gives a range of values compatible with an estimate under the assumptions of a statistical method. Its width reflects both the amount of information in the data and variability. A p-value, when reported, is a measure calculated under a specified null hypothesis and model; it does not describe the size of an effect or establish whether it is important. The registry record does not report a confidence interval, p-value, model, or treatment-effect estimate for the primary outcome. No inference about precision or statistical significance can therefore be made from the posted endpoint description.

For a crossover analysis, the comparison should respect the paired structure of measurements from the same participant. In general, treating observations from the two periods as if they came from unrelated participants would fail to use that pairing and could misstate uncertainty. The record does not name an analysis method or explain how within-participant dependence was addressed. It would be inappropriate to claim that a paired test, mixed model, or any other particular method was used.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model understates variability, standard errors and confidence intervals may be too small and test results may appear more precise than warranted. This concern is especially relevant to some count outcomes, where a simple model may assume a particular relationship between the mean and variance. The primary endpoint in this record is continuous Cmax, and no model or over-dispersion assessment is reported. The concept is general context, not a claim that over-dispersion affected this study.

What can the record establish about the analysis?

The record lists nine outcome measures and zero analysis records. It does not report an analysis population, exclusions, a missing-data method, covariate adjustment, multiplicity control, or a prespecified statistical plan. It also does not report whether any interim analyses were planned or performed. These omissions mean that the analysis cannot be reconstructed from the registry information. They do not establish that such methods were absent from the study protocol or from other documents; those details are simply not reported in the registry record.

The record includes a general planning description for sample-size illustrations, but no resulting planning values are included in the registry record for interpretation. In general, a sample-size calculation is a design aid based on assumed effect size, variability, significance level, and power. It is not a measure of the probability that a completed study detected an effect. No planning value or observed-power claim can be made from the registry record. A sample-size justification for the trial is not reported in the registry record.

In short, the design and the intended summary statistic are identifiable, while the actual statistical analysis and its results are not. Any more specific description of the test, model, assumptions, or treatment contrast would go beyond what the registry record reports.

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("BIA 9-1067 + Warfarin")
n   <- c(20)
m   <- c(196)
sp  <- c(106)
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  BIA 9-1067 + Warfarin  20  196.000  106.000  146.390  245.610

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists nine outcome measures, but does not report a multiplicity strategy. In general, multiplicity arises when several outcomes, comparisons, time points, or analyses are examined. Testing many questions can increase the chance of finding an apparently notable result by chance if no adjustment or prioritization plan is used. A prespecified primary outcome and a clear analysis plan help readers understand which result is confirmatory and how other results should be interpreted. The record identifies a primary outcome title, but does not report the statistical plan, any adjustment method, or how the other measures relate to the primary question.

Numerical results for the primary outcome are not reported in the registry record. The record also contains no analysis records, so it does not state which participants or observations were included in any efficacy analysis. Analysis populations, exclusions, and handling of missing measurements are not reported in the registry record. This matters because missing measurements can affect the composition of the analyzed data and the precision or validity of an estimate. In a crossover study, unavailable data from either period can also affect whether a participant contributes a within-participant comparison. The record does not say whether missingness occurred or how it was addressed.

The registry information does not identify an interim-analysis plan, stopping rule, or statistical monitoring procedure. Those details are not reported in the registry record, and their absence from this record should not be taken as proof that no such procedures existed elsewhere. Without outcome estimates and analysis details, readers cannot assess whether multiplicity, missing data, or the choice of analysis population influenced the reported findings.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety entries list 20 participants at risk in each group. The serious adverse event count is zero for BIA 9-1067 plus warfarin and zero for warfarin. The entries for other adverse events list six affected participants in the combination group and seven in the warfarin group. These are participant counts in the registry record, not estimates of a treatment effect. No statistical comparison or uncertainty measure is reported for these counts.

The record does not provide event-level terms for the other adverse events in the information available, and it does not describe their severity, timing, duration, or relationship to treatment. It is therefore not possible to characterize the types of events or compare their clinical importance. The death fields contain no count; deaths are not reported in the registry record. A blank or unpopulated field should not be read as a reported finding of zero deaths.

In general, safety counts require context about how events were defined, collected, and attributed, as well as the duration of observation. Those details are not reported in the registry record. The counts should be read as the limited descriptive information posted, not as evidence that the treatments have equivalent safety profiles or as a basis for a broader safety conclusion.

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

This record documents a randomized, unmasked, phase one crossover study of BIA 9-1067 with warfarin, including the two treatment sequences and a primary outcome defined as mean Cmax of BIA 9-1067 after co-administration. It also records the stated interest in CYP2C9 inhibition and S-warfarin pharmacokinetics. The available results information does not include numerical values for the primary outcome, a treatment contrast, or an inferential analysis.

Accordingly, the posted record does not establish the size or direction of a pharmacokinetic difference between treatment conditions. It does not provide a confidence interval to assess precision or a p-value to assess compatibility with a statistical null model. The absence of those results is not evidence that the conditions were the same, nor does it show that an effect was present. The registry record simply does not report the analysis needed to distinguish those possibilities.

The listed primary outcome is BIA 9-1067 Cmax with warfarin, whereas the brief summary frames the purpose around S-warfarin pharmacokinetics. No numerical S-warfarin results or CYP2C9 analysis are reported in the registry record. Thus, the stated mechanistic question cannot be resolved from the posted outcome information. The outcome definition alone does not establish a change in enzyme activity or a clinical consequence.

The adverse-event information is limited to counts of participants with serious or other events, without event details or statistical comparisons. It can be described as posted, but cannot support a broad comparative safety conclusion. Likewise, the enrollment and design information describe the study structure but do not substitute for outcome results.

In general, a trial result is interpreted using the estimated contrast, its uncertainty, the analysis assumptions, and the population to which the data apply. Here, those elements are not fully reported. The record supports a description of what was intended to be studied and some safety counts; it does not support claims that BIA 9-1067 did or did not alter warfarin pharmacokinetics, or that one treatment condition was better or worse.

14. Why This Trial Matters Statistically

This study raises a statistical question that is especially suited to a crossover design: how measurements under warfarin alone compare with measurements under co-administration in the same participants. In general, within-participant designs can reduce the influence of stable differences between people, because each participant can contribute information under both conditions. Correct analysis still depends on the paired structure and on accounting for period and possible carryover effects. The registry record gives the sequence order but does not report how those features were analyzed.

The record also illustrates why endpoint labels and study objectives need to be read carefully. Its brief summary focuses on S-warfarin pharmacokinetics and CYP2C9, while its primary outcome title identifies BIA 9-1067 Cmax during co-administration. These describe related pharmacokinetic subject matter but are not the same measurement. The numerical results and analysis that would connect the stated objective to an observed treatment contrast are not reported in the registry record.

Another statistical lesson is the distinction between a completed study and an interpretable result. The record marks the study completed and identifies its enrollment, design, endpoint, and adverse-event counts. Yet it does not post the primary outcome values or analysis. Without an estimate and uncertainty measure, readers cannot assess either the magnitude or precision of the result. A named endpoint and a completed status do not replace those statistical details.

The adverse-event entries also show why counts need context. Counts of participants with events can describe what was recorded, but event definitions, detail, duration, and comparative analyses are needed for fuller interpretation. Overall, the record is useful for identifying the design and intended pharmacokinetic question, while the missing analysis limits what can be concluded statistically.

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 this trial is that numerical primary-outcome results are not reported in the registry record. The record names mean Cmax of BIA 9-1067 with warfarin and specifies a sampling timeframe, but gives no observed mean, standard deviation, or comparator result. It also gives no treatment contrast, confidence interval, or p-value. The size, direction, and precision of a difference therefore cannot be assessed.

The endpoint description and the stated study purpose are not identical in wording: the primary measure is BIA 9-1067 Cmax with warfarin, while the brief summary describes an assessment of S-warfarin pharmacokinetics and CYP2C9 inhibition. Numerical results for S-warfarin and an analysis of CYP2C9 are not reported in the registry record. This limits assessment of whether the posted endpoint addresses the stated pharmacokinetic objective.

Important design and analysis details are also not reported in the registry record, including the interval between periods, any washout procedure, handling of period or carryover effects, statistical model, analysis populations, missing-data methods, and multiplicity strategy. Their absence prevents reconstruction of the planned or performed analysis; it does not establish that no such procedures were used outside the registry record.

The official title describes healthy volunteers, but the conditions listing names Parkinson's Disease (PD), and the record does not explain that difference. Participant eligibility and characteristics are not reported in the registry information described. Safety reporting is limited to counts, without event terms, timing, or a comparative analysis. These limitations constrain both the interpretation of the study population and the conclusions that can be drawn from the posted safety information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Effect of BIA 9-1067 on the Pharmacokinetics and Pharmacodynamics of Warfarin — NCT02169440.
• Registry record last updated 2015-12-22; status last verified 2015-11.
• Results first posted 2015-12-22.
• 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

NCT02169440 is a completed phase one randomized, unmasked crossover study sponsored by Bial - Portela C S.A. The registry record lists an enrollment of 20, a study start of 2009-06, and a primary completion of 2009-07. Its two sequences placed warfarin alone and BIA 9-1067 with warfarin in opposite period orders. The official title describes healthy volunteers; the conditions listing names Parkinson's Disease (PD), without an explanation of the difference.

The stated purpose concerns CYP2C9 inhibition and S-warfarin pharmacokinetics. The primary outcome is mean Cmax of BIA 9-1067 after co-administration with warfarin, measured on a schedule extending through 144 h. Numerical results and statistical analyses for that endpoint are not reported in the registry record. Safety entries list no serious adverse events in either group and report other adverse events for six participants with BIA 9-1067 plus warfarin and seven with warfarin. Event details and death counts are not reported in the registry record.