Pharmacokinetic Interaction Between BIA 9-1067 and Standard-release Levodopa/Carbidopa: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetic Interaction Between BIA 9-1067 and Standard-release Levodopa/Carbidopa (NCT01533077), a randomized phase 1 study. The primary outcome is Cmax - Maximum Observed Plasma Concentration (L-DOPA).

2. Clinical Question

The trial examined pharmacokinetic interaction: how levodopa concentrations in plasma differed when Sinemet® 100/25 mg was administered alone or in relation to BIA 9-1067 50 mg. The primary measure was maximum observed plasma concentration of L-DOPA. The registry describes administration of the medicines concomitantly or with Sinemet® given one hour after BIA 9-1067, as well as a Sinemet®-alone condition.

This is a pharmacokinetic question, not a test of symptom improvement or disease outcomes. Maximum concentration describes the highest observed plasma concentration over the measurement schedule; it does not by itself describe the concentration at every time point, the overall exposure across the full schedule, or a clinical effect. The registry record does not report results on clinical outcomes.

3. Trial Design

The registry identifies this as a completed Phase 1 study with randomized allocation and a crossover model. Masking was none. Enrollment was 18. The listed study dates are 2009-03 for the start and 2009-10 for primary completion. The official title specifies healthy subjects, although Parkinson Disease is also listed among the conditions.

In a crossover design, participants receive more than one treatment condition in an assigned sequence. This allows comparisons to use observations from the same participant under different conditions, which can account for stable differences between participants. That general feature does not establish which statistical model was used in this study. The registry record does not report the statistical model for the posted outcome or how sequence, period, or carryover effects were handled.

The registry describes four groups with different orders of the four treatment conditions: BIA 9-1067 alone, Sinemet® alone, the medicines given together, and Sinemet® given one hour after BIA 9-1067. The sequences vary which condition occurs in each period. The primary outcome population description reports that 18 subjects completed 2 treatment periods, 17 completed 3 treatment periods and 16 completed all 4 treatment periods. The registry does not give a group-by-group account of completion or explain how partial treatment-period data contributed to each comparison.

The intervention descriptions name BIA 9-1067 and Sinemet® 100/25 mg. The primary endpoint is reported as mean L-DOPA pharmacokinetic parameters, with maximum observed plasma concentration as the primary measure. Concentrations were scheduled from pre-dose through 72 h after dose, at the time points listed in the endpoint description. The registry record does not report the original design assumptions, the rationale for the enrollment target, a planned statistical analysis, or whether any interim analyses were conducted.

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

Analysis population for the primary outcome, as defined in the registry: According to the protocol, the "pharmacokinetic population" should include all subjects who had valid data for all treatment periods. In this study, 18 subjects completed 2 treatment periods, 17 subjects completed 3 treatment periods and 16 subjects completed all 4 treatment periods.

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 (L-DOPA), measured over pre-dose, ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72 h after dose..

The primary endpoint is Cmax, defined in the registry as maximum observed plasma concentration of L-DOPA. It is expressed in ng/mL and reported as a mean with standard deviation. L-DOPA is levodopa, the substance whose concentration in plasma the study set out to characterize. The registry description calls these mean pharmacokinetic parameters of L-beta-3,4-dihydroxyphenylalanine (levodopa).

Maximum concentration is used in pharmacokinetic research to describe the peak observed concentration after dosing. In general, it can help characterize the concentration-time profile and compare how that profile changes between dosing conditions. It represents one feature of the profile, rather than the full pattern of concentrations or total drug exposure. The registry also lists scheduled sampling at pre-dose, ½, 1, 1½, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72 h after dose. The endpoint description does not specify how the maximum was determined from those samples.

The posted values are group means and standard deviations. A mean describes the average of the observed values, while the standard deviation describes variation among those values. The registry record does not report individual participant concentrations, the distribution of Cmax values, or other measures of exposure in the results presented for this endpoint. Cmax alone therefore cannot answer questions about concentration at each scheduled time or about outcomes beyond the measured pharmacokinetic endpoint.

7. Results Posted in the Registry

• BIA 9-1067 50 mg + Sinemet® 100/25 mg Separated 1 h: mean 1,105 versus 1,070 on control; difference 35.00 (95% CI -193.98 to 263.98), standardized effect d = 0.10; z-test p = 0.764.
• BIA 9-1067 50 mg + Sinemet® 100/25 mg Concomitantly: mean 1,198 versus 1,070 on control; difference 128.00 (95% CI -84.28 to 340.28), standardized effect d = 0.41; z-test p = 0.237.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports continuous outcome data summarized by means and standard deviations. The primary measure, Cmax, is a continuous concentration measured in ng/mL. The posted results give one mean and standard deviation for each treatment condition, alongside the number of observations contributing to that condition. These summaries describe location and spread; they do not show every participant’s value or the shape of the distribution.

What does a mean difference describe?

A mean difference expresses the contrast between the mean in one condition and the mean in a comparator condition, on the original measurement scale. Here the comparisons use Sinemet® 100/25 mg alone as the comparator. The posted estimate of 35.0 ng/mL contrasts the one-hour-separated condition with Sinemet® alone. The estimate of 128.0 ng/mL contrasts concomitant administration with Sinemet® alone. A positive estimate indicates a higher observed mean in the named combination condition than in the comparator, as represented by these posted summaries. These are unadjusted estimates and should not be mistaken for a model-adjusted crossover effect.

What does a confidence interval add?

A confidence interval communicates uncertainty around an estimated difference. In general, a wider interval indicates less precision, while a narrower interval indicates greater precision, given the assumptions of the method used. The interval for the separated condition extends from -194.0 to 264.0 ng/mL; the interval for the concomitant condition extends from -84.28 to 340.3 ng/mL. Both contain zero, which means the intervals include no difference as a plausible value under the calculation used. They also include positive and negative differences, so they do not pin down the direction or magnitude of the underlying contrast.

The record does not identify the method used to calculate the confidence intervals. The comparisons include pooled standard deviations and standard errors, but the registry does not state that these are from the prespecified crossover analysis. In general, a crossover analysis can use the fact that each participant receives multiple conditions. An analysis based only on independent group summaries may not use the within-participant correlation. The registry does not provide the participant-level data or enough model detail to determine how the posted comparison estimates relate to the randomized sequences and repeated measurements.

How should the p-values be read?

The reported p-values are 0.764 for the one-hour-separated comparison and 0.237 for the concomitant comparison. In general, a p-value measures how surprising data at least as incompatible with a specified null hypothesis would be, assuming that hypothesis and the statistical model were correct. It is not the probability that the null hypothesis is true, nor does it measure the probability that a result is due to chance. Here the values are explicitly unadjusted. The registry record does not report the full testing strategy, the chosen significance threshold for the trial’s own analysis, or a multiplicity adjustment. The p-values therefore should be read as reported comparisons, not as a complete account of confirmatory inference.

Why does the crossover structure matter?

In general, crossover studies can improve efficiency because a participant can serve as their own comparator. The precision of a within-participant contrast depends on the variability of the differences within participants, not just on the separate standard deviations for each treatment condition. A crossover study also requires attention to period effects, treatment order and potential carryover. The registry lists randomized sequences across four periods, but does not report how these design features were addressed in the analysis. It is not possible to infer a particular model or adjustment from the group means and standard deviations.

Different numbers of observations are reported for the three primary-outcome conditions: 17 for Sinemet® alone, 18 for the one-hour-separated condition and 16 for concomitant administration. These are the posted outcome group sizes, not a statement that the same participants contributed to all conditions. The population description says that subjects completed differing numbers of treatment periods and defines the protocol pharmacokinetic population by valid data for all treatment periods. The record does not explain whether the analysis used that population exactly, whether partial records were included, or how missing values were treated.

What is over-dispersion, and is it relevant?

In general, over-dispersion means that observed variability is greater than expected under a statistical model. It is a concern in some outcome types, such as counts, when a model assumes less variability than the data contain. The primary measure is continuous, and the record summarizes it using standard deviations. It does not report a count model, an over-dispersion assessment, or an adjustment for over-dispersion. This general concept does not establish that over-dispersion occurred in this study.

The record also lists 16 outcome measures but reports no secondary results. Its primary-outcome information identifies the measure, unit, summary statistic and sampling schedule, but the record does not report a full statistical analysis plan or a detailed account of the calculation procedures. As a result, the most defensible interpretation stays close to the posted summaries and unadjusted comparisons. General statistical explanations describe how these quantities are usually understood; they do not fill in analysis choices that the registry record does not report.

10. Confidence Intervals and Precision

The reported mean differences are accompanied by confidence intervals that are wide relative to the point estimates. For the one-hour-separated comparison, the estimated difference was 35.0 ng/mL, and the interval ranges from -194.0 to 264.0 ng/mL. For concomitant administration, the estimate was 128.0 ng/mL, and the interval ranges from -84.28 to 340.3 ng/mL. Each interval spans zero and includes values on both sides of zero.

A confidence interval is a range of values compatible with the observed data under the method’s assumptions. In general, its width reflects sampling uncertainty and the precision of the estimate. The intervals do not establish that the true difference is zero, and they do not rule out all potentially meaningful differences. The registry record does not define what magnitude of Cmax difference would be considered meaningful, so the clinical importance of values within these ranges cannot be determined from the reported results alone.

The analysis groups are small: 17 for Sinemet® alone, 18 for the one-hour-separated condition and 16 for concomitant administration. The standard deviations are 328.0, 363.0 and 294.0 ng/mL, respectively. These summaries indicate variation in observed concentrations, but do not reveal the detailed distribution or the within-participant correlation that is relevant to a crossover comparison. The record does not provide confidence intervals for the individual condition means.

Precision is also affected by incomplete treatment-period completion: 18 subjects completed 2 periods, 17 completed 3 periods and 16 completed all 4 periods. The registry record does not report the missing-data method or the exact set of participants used in each comparison. Consequently, the intervals should be interpreted as reported, with the understanding that their calculation assumptions and handling of incomplete crossover data are not fully described.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for 80% power and participants per arm for 90% power. These are planning illustrations based on the observed effect, not the original design assumptions for this trial. The registry record does not report the trial’s own sample-size justification or original planning assumptions.

The stated illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The rows describe planning for 100% of the observed effect, planning for 75% of the observed effect, and planning for 50% of the observed effect. The values are shown separately for the one-hour-separated comparison and the concomitant comparison.

The 80% power column gives the planned participants per arm for a design with 80% probability of detecting the specified effect under those assumptions, if that effect is present. The 90% power column gives the corresponding number for a design with 90% probability. These are theoretical design characteristics, not probabilities that the posted finding is correct. The figures are not observed power.

For each comparison, the planning numbers increase as the targeted effect becomes smaller. In general, a smaller effect is harder to distinguish from random variation and requires more participants to reach the same planned power, all else equal. These illustrations use the observed effects from this small study as their starting point; they should not be read as an independently justified sample-size recommendation. The registry does not report whether the study was designed around these effects, these assumptions or these target power levels.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 35.000; pooled standard deviation σ = 346.472.
2. n = 2 × (1.96 + 0.842)² × 346.472² / 35.000² = 1,538.3, rounded up to 1,539 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 35                      # observed difference in means
sigma <- 346.47213364705                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1533077)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 1,539 (80% power), 2,060 (90% power)
 75% of observed effect: n per arm = 2,735 (80% power), 3,662 (90% power)
 50% of observed effect: n per arm = 6,154 (80% power), 8,238 (90% power)
power.t.test: 1539.3 
Simulated power at n = 1,539 per arm: 0.805 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The record reports one primary outcome measure, Cmax, and two posted comparisons against Sinemet® 100/25 mg alone. Their p-values are unadjusted. The registry record does not report a prespecified multiplicity strategy, whether the comparisons were treated as co-primary, or whether any adjustment was planned or performed. When multiple comparisons are considered, the chance of at least one small p-value can increase; in general, methods to control that issue depend on the questions and testing plan. No adjustment should be assumed.

The record lists 16 outcome measures, with no secondary results posted. It does not identify whether the listed measures were all planned, how they were prioritized, or whether there were additional analyses that were not reported. The primary endpoint is described as mean L-DOPA pharmacokinetic parameters, and the main posted result concerns maximum observed plasma concentration. The record does not give a complete statistical analysis plan or identify the exact methods used for the primary comparisons.

The protocol population definition says that the pharmacokinetic population should include subjects with valid data for all treatment periods. The record then reports that 18 subjects completed 2 treatment periods, 17 completed 3 periods and 16 completed all 4 periods. This establishes that the completion record varies by treatment-period coverage; it does not state how many observations were used for every analysis or how incomplete records were handled. A missing-data method, imputation approach or sensitivity analysis is not reported in the registry record.

The outcome group sizes differ by condition, and the registry does not explain whether those differences reflect missing concentration data, treatment-period completion or another feature of analysis eligibility. It also does not report whether the primary estimates account for within-participant pairing, sequence or period. These omissions limit assessment of bias and uncertainty in the comparisons. The record’s data allow readers to describe the posted means, standard deviations, confidence intervals and unadjusted p-values, but not to reconstruct the full analysis population or establish the robustness of the conclusions to alternative analysis choices.

14. 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 registry reports serious adverse events affecting 0 participants in each listed treatment group: BIA 9-1067 50 mg, the one-hour-separated combination, the concomitant combination, and Sinemet® 100/25 mg alone. The numbers at risk listed for these groups are 18, 18, 16 and 17, respectively. No serious adverse event terms are listed in the record.

These are group-specific reported counts. They should not be added together because the study used a crossover design and participants could receive more than one condition. The figures do not describe the timing, duration or severity of non-serious events. Other adverse events affected 8 participants in the BIA 9-1067-alone group, 10 in the one-hour-separated group, 8 in the concomitant group and 8 in the Sinemet®-alone group. The registry record does not provide event terms for those counts in the registry record reported for this page.

Deaths are not reported in the registry record. The serious-event counts are descriptive and should be interpreted in light of the study’s small groups and limited information on event definitions and follow-up. A count of zero reported serious events in a group does not establish that an event could not occur under other conditions or in a larger population.

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

The posted primary-outcome results describe mean maximum L-DOPA plasma concentrations for Sinemet® alone and for two dosing conditions involving BIA 9-1067. The reported means were 1070.0 ng/mL for Sinemet® alone, 1105.0 ng/mL when Sinemet® followed BIA 9-1067 by one hour, and 1198.0 ng/mL when the medicines were administered concomitantly. The corresponding unadjusted mean differences from Sinemet® alone were 35.0 ng/mL and 128.0 ng/mL.

Those differences are estimates, not proof of a stable or clinically important effect. Both confidence intervals include zero and extend across positive and negative differences. The p-values are unadjusted, and the registry does not report enough detail to assess the full crossover analysis. The results therefore show the observed summaries and the uncertainty around the posted contrasts, rather than establishing equivalence or a definite difference between conditions.

The question studied is pharmacokinetic. Cmax characterizes the maximum observed plasma concentration, and the results do not establish what happened to concentrations at every time point, overall exposure, symptoms, disease progression or other clinical outcomes. The record’s official title describes healthy subjects; Parkinson Disease is listed as a condition. The findings should be understood within the recorded study context, not generalized to populations or outcomes that the results do not report.

The trial enrolled 18 subjects and the completion counts vary across treatment periods. The endpoint groups contain 16 to 18 observations, and confidence intervals are broad. Those features leave substantial uncertainty about the magnitude and direction of any underlying contrast. The registry record does not report a threshold for a meaningful Cmax difference, the full analysis plan, or missing-data methods. No clinical conclusion should be inferred from the concentration summaries alone.

16. Why This Trial Matters Statistically

This study illustrates why a pharmacokinetic result needs to be read with its design and analysis population in mind. A crossover trial assigns treatment conditions in sequences, allowing comparisons within participants in principle. That structure can be informative, but interpretation depends on how repeated observations, treatment order, period effects and incomplete periods are handled. The registry describes randomized sequences but does not report the analysis details needed to assess those issues.

It also shows the difference between a point estimate and its precision. The posted mean differences are positive, but both confidence intervals include zero and cover values in both directions. The point estimate alone does not settle whether the underlying difference is small, large, or absent. Reporting the interval makes the uncertainty visible, while the incomplete analysis description limits how fully the calculation can be evaluated.

The posted group sizes and completion details are not interchangeable. The primary outcome summaries report different numbers of observations by condition, while the protocol population description refers to valid data across all treatment periods. Understanding how those populations relate is essential when interpreting estimates from a crossover study. The registry record does not provide that reconciliation.

Finally, the endpoint is a concentration measure, not a clinical outcome. Keeping that distinction clear prevents a pharmacokinetic comparison from being mistaken for evidence about symptoms or other patient outcomes. The record offers a focused set of observations, but the broad intervals, small groups and unreported analysis details mean that the quantitative interpretation should remain cautious and specific to the measured endpoint.

17. 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 gives a limited account of the analysis. It does not report the statistical model used for the crossover data, including how within-participant correlation, sequence, period or possible carryover was addressed. It also does not report a full statistical analysis plan, a prespecified multiplicity approach, or an explanation of the confidence-interval calculation. The posted p-values are unadjusted.

The protocol description defines the pharmacokinetic population as subjects with valid data for all treatment periods, while completion counts differ across periods. The record does not explain how participants with incomplete periods were treated in the endpoint analysis, how missing measurements were handled, or whether sensitivity analyses were performed. The endpoint group sizes vary across conditions, and the exact overlap of participants is not reported.

The record lists 16 outcome measures but reports no secondary results. It also does not report individual-level data, detailed concentration profiles, or a criterion for a meaningful difference in Cmax. The outcome summary therefore cannot address the distribution of values or the full time course beyond the listed sampling schedule and endpoint definition.

The study is a completed Phase 1 crossover trial with enrollment of 18. The posted analysis groups are small, and the confidence intervals are broad. Results are from healthy subjects according to the official title, while Parkinson Disease is also listed as a condition. The registry record does not explain this condition listing. Its results concern the specified pharmacokinetic measure and dosing conditions; they do not report clinical outcomes.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Pharmacokinetic Interaction Between BIA 9-1067 and Standard-release Levodopa/Carbidopa — NCT01533077.
• 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.

21. Record Summary

NCT01533077 is a completed randomized, unmasked, Phase 1 crossover study of BIA 9-1067 and standard-release levodopa/carbidopa. Its official title describes a pharmacokinetic interaction study in healthy subjects. The registry lists Parkinson Disease as a condition and reports enrollment of 18.

The primary endpoint was mean maximum observed plasma concentration of L-DOPA, measured in ng/mL. The posted comparisons use Sinemet® 100/25 mg alone as the comparator. The one-hour-separated comparison had a mean difference of 35.0 ng/mL, with a 95% confidence interval from -194.0 to 264.0 and p = 0.764. The concomitant comparison had a mean difference of 128.0 ng/mL, with a 95% confidence interval from -84.28 to 340.3 and p = 0.237.

The registry record does not report the full crossover analysis plan, handling of missing treatment-period data, or multiplicity strategy. The estimates are unadjusted, and their confidence intervals include zero.