Study of BIA 9-1067 to Investigate Its Effect on Levodopa Pharmacokinetic: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of BIA 9-1067 to Investigate Its Effect on Levodopa Pharmacokinetic (NCT01519284), a randomized phase 1 study. The primary outcome is Cmax - Maximum Plasma Concentration of Levodopa.

2. Clinical Question

3. Trial Design

This was a phase 1, randomized, double-blind, parallel-group, placebo- and active-controlled study sponsored by Bial - Portela C S.A. The registry reports enrollment of 82 participants. The study started in 2009-11, primary completion was in 2010-02, and its status is completed.

Five dosing groups are described. Group 1 received placebo throughout. Groups 2, 3, and 4 received BIA 9-1067 5 mg, 15 mg, or 30 mg once daily, respectively, with placebo at the other specified dosing times during the first seven days. Group 5 received entacapone 200 mg three times daily with placebo at the morning dosing time. On Day 8, each active-treatment group received levodopa/carbidopa 100/25 mg with its assigned treatment regimen; Group 1 received placebo with levodopa/carbidopa.

The primary endpoint was measured following a single oral administration of levodopa/carbidopa on Day 8, after the repeated-treatment period. The timeframe is reported as 8 days. The primary endpoint results list 16 participants in each of the five groups. The record does not report why the total enrollment differs from the number listed for the primary endpoint, or whether the same participants contributed to every endpoint.

Randomization and double masking are recorded, but the method used to generate the allocation sequence, conceal allocation, or maintain masking is not reported in the registry record. Further operational details, including site information and the trial's original sample-size justification, 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.

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 Plasma Concentration of Levodopa, measured over 8 days.

The primary endpoint is Cmax, the maximum plasma concentration of levodopa, measured in ng/mL after a single oral dose of levodopa/carbidopa 100/25 mg on Day 8. In this study, Cmax was used to describe the peak concentration observed after the dose, following repeated dosing with BIA 9-1067, entacapone, or placebo.

Pharmacokinetic measures help characterize how a drug exposure changes across treatment conditions. Cmax focuses on the observed peak, while other measures can describe the timing of that peak or overall exposure over a sampling period. These are distinct properties: a difference in peak concentration does not by itself establish a difference in total exposure, timing, symptoms, or clinical outcomes.

The registry reports group means and standard deviations for Cmax, along with comparisons against the placebo group. Mean differences therefore describe the difference between the groups' average concentrations, not the change experienced by every participant. The record does not report a threshold for a clinically meaningful Cmax difference or a prespecified interpretation rule for this endpoint.

7. Results Posted in the Registry

• Group 2: mean 1,106 versus 1,076 on control; difference 30.00 (95% CI -220.96 to 280.96), standardized effect d = 0.08; z-test p = 0.815.
• Group 3: mean 943.00 versus 1,076 on control; difference -133.00 (95% CI -347.42 to 81.42), standardized effect d = -0.43; z-test p = 0.224.
• Group 4: mean 981.00 versus 1,076 on control; difference -95.00 (95% CI -374.04 to 184.04), standardized effect d = -0.24; z-test p = 0.505.
• Group 5: mean 928.00 versus 1,076 on control; difference -148.00 (95% CI -335.03 to 39.03), standardized effect d = -0.55; z-test p = 0.121.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

AUC0-t - Area Under the Plasma Concentration-time Curve (AUC) of Levodopa From Time Zero to the Last Sampling Time at Which the Drug Concentration Was at or Above the Lower Limit of Quantification.

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Group 2: mean 1,785 versus 1,578 on control; difference 207.00 (95% CI -115.42 to 529.42), standardized effect d = 0.44; z-test p = 0.208.
  • Group 3: mean 2,102 versus 1,578 on control; difference 524.00 (95% CI 203.80 to 844.20), standardized effect d = 1.13; z-test p = 0.001.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group 2 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Group 3 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

AUC0-∞ - Area Under the Plasma Concentration-time Curve (AUC) of Levodopa From Time Zero to Infinity

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Group 2: mean 1,873 versus 1,649 on control; difference 224.00 (95% CI -95.26 to 543.26), standardized effect d = 0.49; z-test p = 0.169.
  • Group 3: mean 2,233 versus 1,649 on control; difference 584.00 (95% CI 261.73 to 906.27), standardized effect d = 1.26; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Group 2 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Group 3 than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes address other dimensions of levodopa pharmacokinetics. AUC0-t and AUC0-∞ summarize exposure over time, whereas Cmax describes the maximum measured concentration and Tmax describes when that maximum is reached. In general, measures of peak concentration, timing, and overall exposure may show different patterns because they capture different features of a concentration-time profile.

The posted AUC group summaries show higher means in several active-treatment groups than in placebo, while the primary Cmax comparisons do not show a clearly separated group difference in their confidence intervals. This broad contrast illustrates why the primary and secondary endpoints should not be treated as interchangeable. The registry does not provide numerical Tmax results, and the numerical AUC comparisons are not posted for every treatment group. No further inference about a dose pattern or endpoint relationship is warranted from the incomplete set of comparisons.

Unadjusted secondary findings carry less weight when multiple outcomes and comparisons are considered. General explanation: testing many hypotheses increases the chance that at least one result appears statistically notable by chance, unless an appropriate strategy is used to control that risk. The registry does not report a multiplicity strategy, a hierarchy of outcomes, or a confirmatory status for the secondary analyses. The AUC p-values should therefore be treated as exploratory evidence rather than definitive confirmation. Their estimates and intervals remain informative descriptions, but the analysis record is insufficient to establish how they were planned or interpreted alongside the primary endpoint.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Tmax - Time to Reach Maximum Plasma Concentration of Levodopa
• AUC0-t - Area Under the Plasma Concentration-time Curve (AUC) of Levodopa From Time Zero to the Last Sampling Time at Which the Drug Concentration Was at or Above the Lower Limit of Quantification.
• AUC0-∞ - Area Under the Plasma Concentration-time Curve (AUC) of Levodopa From Time Zero to Infinity

9. Statistical Interpretation

10. Statistical Methods Explained

What do the group summaries describe?

The primary endpoint is continuous, so it can take a range of measured values rather than belonging to a small set of categories. The registry reports the mean Cmax for each group, together with the standard deviation. A mean is the arithmetic average of the observations in a group. The standard deviation describes how dispersed individual measurements are around that average. It is not the uncertainty around the mean; uncertainty in a mean comparison is instead conveyed by its confidence interval.

The groups each have 16 participants in the primary endpoint results. Similar group sizes make the descriptive summaries straightforward to compare, but they do not remove uncertainty caused by variability within the groups. Randomization can support comparisons by helping balance participant characteristics on average, but details of the randomization method and the analysis population are not reported in the registry record.

What does a mean difference mean?

For each reported primary comparison, the placebo-group mean is contrasted with the mean in one other group. A positive difference means the other group's reported mean is higher than the placebo mean; a negative difference means it is lower. The estimate is a difference between group averages, not an individual-level treatment effect and not a percentage change.

The comparisons are identified as unadjusted and are simple recalculations from posted summary statistics. They use the reported group means and variability, without adjustment for other variables. A randomized trial may also use an investigator-specified model or analysis procedure, but that statistical plan and any sponsor-reported analysis are not reported in the registry record. No discrepancy is indicated for the posted values.

How should the p-values be read?

General explanation: a p-value describes how compatible the observed data are with a specified null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not quantify the size or clinical importance of a difference. The reported p-values are unadjusted. For the primary endpoint, each is greater than 0.05; those values should be considered alongside the estimates and confidence intervals rather than as a stand-alone verdict.

The record does not report the investigators' testing procedure, a prespecified significance threshold, or a plan for handling the several comparisons. The posted p-values therefore do not establish whether the sponsor used the same methods or how the results were interpreted in the full trial analysis.

Why are variability and precision important?

General explanation: when individual measurements vary widely, the group mean can be estimated less precisely, especially when group sizes are small. Standard deviations and confidence intervals provide different views of this issue. The standard deviation describes spread among observed measurements; a confidence interval describes uncertainty around an estimated comparison, given the method and assumptions used to construct it.

The primary group standard deviations differ across groups, and the confidence intervals for the four comparisons are broad. This means the posted summaries are compatible with more than one possible underlying group difference. A result that does not reach a conventional significance threshold is not proof of no effect. Similarly, a nonzero estimate alone does not establish a reliable or clinically important difference.

What do the secondary measures add?

The secondary outcomes include Tmax, the time to maximum plasma concentration, and two measures of area under the concentration-time curve: AUC0-t and AUC0-∞. AUC measures summarize concentration over time, with AUC0-t ending at the last qualifying sampling time and AUC0-∞ extending to infinity. These measures address aspects of exposure that are related to, but not identical to, Cmax.

The registry lists four outcome measures in total, but numerical secondary results are posted for the two AUC measures and not for Tmax. Secondary results do not have reported analyses in the registry record. The posted comparisons for the AUC measures are unadjusted recalculations from summary statistics. Their interpretation should account for the number of outcomes and comparisons and the absence of a reported multiplicity plan.

What does over-dispersion mean in general?

General explanation: over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model underestimates variability, standard errors may be too small and confidence intervals too narrow, making evidence appear more precise than it is. The registry does not report a model-based dispersion assessment for these continuous outcomes, so there is no basis for concluding that over-dispersion was tested or corrected. For these results, the reported standard deviations show the observed spread, while the registry does not document further modeling details.

11. Confidence Intervals and Precision

Confidence intervals communicate the uncertainty around a comparison estimate. General explanation: a 95% confidence interval is produced by a method designed to cover the underlying value in 95% of repeated samples when its assumptions hold. It is not a range guaranteed to contain the true value in this particular study.

For the primary Cmax comparisons, each 95% confidence interval crosses zero. The intervals extend from -221.0 to 281.0 for BIA 9-1067 5 mg, from -347.4 to 81.42 for 15 mg, from -374.0 to 184.0 for 30 mg, and from -335.0 to 39.03 for entacapone. Thus, the posted results allow for both lower and higher average Cmax than placebo across the intervals. The point estimates alone cannot resolve that uncertainty.

The intervals are wide relative to the estimates, and the primary groups each contain 16 participants. Together, these features indicate limited precision for distinguishing the group means. A wide interval does not prove that a difference exists, just as an interval crossing zero does not prove that there is no difference. Whether the range is clinically important cannot be assessed from the record because a meaningful-difference threshold is not reported in the registry record.

These intervals accompany simple unadjusted comparisons. The registry does not report whether they match an analysis specified in the trial protocol or whether additional adjustments were used by the sponsor. Interpretation should therefore remain tied to the descriptive results and their stated calculation basis.

12. 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 the continuous-outcome comparisons; they are not total event counts. They illustrate what a two-arm study might require under the stated assumptions, using the observed effect or a stated fraction of that effect. These calculations are planning illustrations, not observed power.

The listed assumptions are 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 100%, 75%, or 50% of the observed effect. For each effect size, the figures give participants per arm for 80% power and participants per arm for 90% power. In plain terms, 80% power describes the probability of detecting an effect of the specified size under the planning assumptions if that effect is present; the 90% column uses a higher target probability and consequently requires more participants.

Smaller target effects need more participants because they are harder to distinguish from random variation. The illustrations are based on the observed effect in this study, so they should not be treated as the trial's original design requirements or as a guarantee for a future study. The original sample-size justification and planning assumptions are not reported in the registry record. These figures do not describe the power actually achieved in this trial.

13. 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 = 30.000; pooled standard deviation σ = 362.164.
2. n = 2 × (1.96 + 0.842)² × 362.164² / 30.000² = 2,287.7, rounded up to 2,288 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 <- 30                      # observed difference in means
sigma <- 362.163899360497                     # 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(1519284)
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 = 2,288 (80% power), 3,063 (90% power)
 75% of observed effect: n per arm = 4,068 (80% power), 5,445 (90% power)
 50% of observed effect: n per arm = 9,151 (80% power), 12,251 (90% power)
power.t.test: 2288.7 
Simulated power at n = 2,288 per arm: 0.799 (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.

14. Multiplicity, Missing Data and Analysis Populations

The primary results compare four treatment groups with a common placebo group. The secondary outcomes add further measures and comparisons. When several hypotheses are tested, the overall chance of at least one false-positive finding can rise. Statistical methods can address this issue through procedures such as adjustment or a prespecified testing hierarchy, but the registry record does not report whether any such method was planned or used.

The posted p-values are unadjusted. They should not be read as if a multiplicity adjustment had been applied. The statistical analysis plan, the prespecified primary and secondary hypothesis structure, any interim analyses, and the criteria used to interpret multiple comparisons are not reported in the registry record. The registry lists zero reported analyses, so the posted comparison estimates should be distinguished from a fully documented sponsor analysis.

Information about missing data is also limited. The registry does not report the number of participants with missing endpoint measurements, how missing values were handled, or whether sensitivity analyses were performed. Although the primary endpoint summaries list 16 participants in each group and the registry reports total enrollment of 82, the record does not explain the relationship between those counts or establish that all enrolled participants contributed to every outcome.

The analysis population is not reported in the registry record. It is therefore unclear whether the endpoint summaries represent all randomized participants, participants who completed treatment, or another defined population. Details of protocol deviations and exclusions are not reported in the registry record. These omissions limit assessment of potential bias from missing measurements or analysis-population choices.

15. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: spontaneous abortion (5.9%).

The registry reports serious adverse events for groups at risk: zero affected participants in Groups 1, 2, 4, and 5, and one affected participant among 17 at risk in Group 3. These are counts of participants with a serious adverse event, not counts of all events. The registry also lists spontaneous abortion at 5.9% among the serious-event terms. The record does not provide enough detail to connect that term to a particular group or to interpret the percentage's denominator.

Other adverse events are reported separately: 6 participants in Group 1, 9 in Group 2, 10 in Group 3, 12 in Group 4, and 7 in Group 5 were affected. These counts should not be conflated with serious adverse events. Deaths are not reported in the registry record.

These descriptive counts come from groups with small numbers of participants. They cannot establish whether differences between groups are due to treatment or chance, and the record does not provide a comparative safety analysis. The figures describe what was reported during this study, not the full range or frequency of possible risks.

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

The results describe levodopa concentration measurements after a single levodopa/carbidopa dose on Day 8, following repeated exposure to BIA 9-1067, entacapone, or placebo. For the primary endpoint, the posted group means and comparisons show estimates that vary in direction and uncertainty. Each confidence interval includes zero, and the intervals remain compatible with differences in either direction.

This pattern does not demonstrate that the treatments produce identical Cmax values. Establishing equivalence would require a prespecified margin and an analysis designed for that question; neither is reported in the registry record. Nor do the estimates alone establish a reliable difference. The study's primary endpoint summaries are based on 16 participants in each group, and the comparisons have limited precision.

The endpoint is pharmacokinetic. It describes drug concentration, not symptom improvement, function, quality of life, or disease progression. The registry condition is Parkinson Disease, but the primary endpoint description identifies healthy subjects. These posted measurements cannot by themselves establish clinical effects in people with Parkinson Disease.

Secondary exposure measures may add context about concentration over time, but their results are incomplete in the registry record, and a multiplicity plan is not reported. The posted safety counts are descriptive and do not support a firm comparative safety conclusion. The overall meaning is therefore bounded: these are small-group pharmacokinetic observations, with uncertainty around the primary comparisons and limited documentation of the analysis plan.

17. Why This Trial Matters Statistically

This trial illustrates the distinction between a measured pharmacokinetic outcome and a clinical outcome. Cmax captures the peak plasma concentration of levodopa after dosing. It can answer a focused exposure question, but it does not directly answer whether participants experienced a clinical benefit or harm.

It also demonstrates why estimates, confidence intervals, and p-values should be read together. A point estimate gives the direction and magnitude of the observed group contrast; a confidence interval conveys its uncertainty; and a p-value is a measure tied to a statistical test and its assumptions. In these results, the intervals are broad and include zero, so the data do not precisely determine the direction or size of the primary group differences.

The secondary endpoints show why multiple outcome measures need a clear analysis plan. Measures of peak concentration, timing, and overall exposure describe related but different features. Without a reported hierarchy or multiplicity approach, secondary p-values have a more exploratory interpretation.

Finally, a completed registry record may contain outcome summaries without the details needed to reproduce or fully evaluate the trial analysis. Here, the original sample-size rationale, analysis population, missing-data methods, and multiplicity plan are not reported in the registry record. These omissions matter when judging how strongly descriptive results support broader conclusions.

18. 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 primary endpoint summaries list 16 participants per group, while the total enrollment is 82. The registry does not explain this difference or report how many enrolled participants contributed to each endpoint. The analysis population and any exclusions are not reported in the registry record.

The study is identified as phase 1 and describes healthy subjects, limiting what the pharmacokinetic measurements can say about clinical outcomes in people with Parkinson Disease. The registry condition label does not resolve this distinction. The trial does not report symptom or functional outcomes in the results.

The primary comparisons are unadjusted recalculations from summary statistics, and the registry lists no reported analyses. Details of the sponsor's statistical model, the randomization procedure, missing-data handling, and any sensitivity analyses are not reported in the registry record. The plan for multiple primary and secondary comparisons is also not reported.

Numerical results for Tmax are not reported in the registry record. The AUC comparisons are incomplete across treatment groups, and the record does not give a clinically meaningful threshold for interpreting the size of pharmacokinetic differences. The observed-effect planning illustrations should not be confused with the trial's original sample-size rationale, which is not reported in the registry record.

Finally, the adverse-event results are descriptive, and deaths are not reported in the registry record. The small groups and limited detail on serious-event terms constrain comparative interpretation. These limitations mean the record supports a cautious description of the reported measurements, not broad conclusions about clinical effectiveness or safety.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Study of BIA 9-1067 to Investigate Its Effect on Levodopa Pharmacokinetic — NCT01519284.
• Registry record last updated 2015-08-20; status last verified 2015-07.
• Results first posted 2015-08-20.
• 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.

22. Record Summary

NCT01519284 is a completed phase 1 randomized, double-blind, parallel-group study sponsored by Bial - Portela C S.A. It enrolled 82 participants and investigated repeated dosing of BIA 9-1067 compared with placebo and entacapone, followed by a single levodopa/carbidopa dose on Day 8.

The primary outcome was maximum plasma concentration of levodopa. The reported primary group means each include 16 participants, and all four unadjusted comparison confidence intervals include zero. The registry also reports selected AUC results, but numerical Tmax results are not reported in the registry record.

The record does not report the original sample-size justification, analysis population, missing-data methods, or multiplicity plan. The findings are pharmacokinetic observations and do not directly establish clinical outcomes.