This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Pharmacokinetic-pharmacodynamic Interaction Between Each of Three Different Single Doses of BIA 9-1067 and a Single-dose of Controlled-release 100/25 mg Levodopa/Carbidopa (NCT02169453), a randomized phase 1 study. The primary outcome is Cmax - Maximum Observed Plasma Concentration.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02169453 |
| Phase | Phase 1 |
| Condition | Parkinson's Disease (PD) |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Double |
| Enrollment | 12 |
| Arms in the primary outcome | 4 |
| Lead sponsor | Bial - Portela C S.A. |
| Results posted | Yes |
2. Clinical Question
Population
Healthy male subjects were enrolled in a Phase 1 study. Parkinson's disease is listed as a condition, but the official title describes the participants as healthy male subjects; the registry record does not identify a patient population with Parkinson's disease.
Intervention
At separate treatment periods, participants received a single oral dose of BIA 9-1067 at 25 mg, 50 mg or 100 mg, taken concomitantly with a single dose of controlled-release levodopa/carbidopa 100/25 mg.
Comparator
The comparator was placebo given with the same single dose of controlled-release levodopa/carbidopa 100/25 mg. Each treatment sequence included the active doses and placebo across the four treatment periods.
Primary question
The primary question was whether levodopa maximum observed plasma concentration, or Cmax, differed when each BIA 9-1067 dose was co-administered rather than placebo. The registry record reports means and standard deviations for each treatment and unadjusted mean-difference comparisons.
This is a pharmacokinetic-pharmacodynamic interaction study, but the posted primary endpoint is pharmacokinetic: the maximum observed concentration of levodopa in plasma. The brief summary describes the aim as investigating the effect of the three single doses of BIA 9-1067 on levodopa pharmacokinetics when used with controlled-release levodopa/carbidopa. The comparison is therefore about concentration measurements under the specified co-administration conditions, not a clinical outcome of Parkinson's disease.
The record reports an enrollment of 12 and describes a randomized, double-blind, four-way crossover study. The treatment sequences assign the three BIA 9-1067 doses and placebo across treatment periods, with levodopa/carbidopa given concomitantly. This design allows treatment conditions to be compared within a crossover framework, although the posted summary comparisons do not report a paired treatment-effect analysis.
3. Trial Design
The study is listed as Phase 1, randomized, double-blind, placebo-controlled and crossover. Its official title describes a four-way crossover study in healthy male subjects. Enrollment was 12. The registry record lists Parkinson's disease as a condition, while the trial title and summary identify healthy male subjects; the record does not describe the participants as people being treated for Parkinson's disease.
Participants were assigned to treatment sequences covering four treatment periods. Across these periods, the sequence descriptions include BIA 9-1067 25 mg, 50 mg and 100 mg, as well as placebo. Each was administered concomitantly with a single dose of controlled-release levodopa/carbidopa 100/25 mg. The sequences differ in the order of the treatments. The record states that participants were to attend four treatment periods, but it does not report further details about period length, washout intervals, or how sequence assignment was generated.
Double masking means the registry identifies the study as blinded for two parties, but does not state which roles were masked. The record gives no further operational description of how masking was maintained. It lists BIA 9-1067, placebo and Sinemet CR 100/25 as interventions.
The study is marked completed. The recorded start is 2008-10 and the primary completion is 2009-01. These dates provide registry context rather than evidence about the timing or completeness of any individual participant's measurements. The registry record does not report the original sample-size rationale, analysis model for the crossover structure, or detailed analysis populations. The endpoint results are posted as treatment-specific means and standard deviations, alongside simple unadjusted mean-difference calculations against placebo.
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
| Stage | Group 1 | Group 2 | Group 3 | Group 4 |
|---|---|---|---|---|
| STARTED | 3 | 3 | 3 | 3 |
| 25 mg BIA 9-1067 | 3 | 3 | 3 | 3 |
| 50 mg BIA 9-1067 | 3 | 3 | 2 | 3 |
| 100 mg BIA 9-1067 | 3 | 3 | 3 | 3 |
| Placebo | 3 | 3 | 3 | 3 |
| COMPLETED | 3 | 3 | 2 | 3 |
| NOT COMPLETED | 0 | 0 | 1 | 0 |
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.
| Characteristic | Unit | Group 1 | Group 2 | Group 3 | Group 4 | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 3 | 3 | 3 | 3 | 12 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 3 | 3 | 3 | 3 | 12 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | 0 | 0 | 0 | 0 | 0 |
| Sex: Female, Male: Male | Participants | 3 | 3 | 3 | 3 | 12 |
6. Primary Endpoint
The registry lists the primary outcome as Cmax - Maximum Observed Plasma Concentration, measured over pre-dose, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 48 and 72 h post-dose.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | ng/mL |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is levodopa Cmax, the maximum observed plasma concentration. It is a continuous pharmacokinetic measure: the registry reports the mean and standard deviation in ng/mL for each treatment condition. Cmax captures the highest measured levodopa concentration over the scheduled sampling window; the record gives measurements from pre-dose through 72 h post-dose at specified time points.
This measure is used to describe how high the observed plasma concentration becomes after dosing. In a drug-interaction study, comparing Cmax under co-administration with the comparator condition can help characterize whether exposure differs in its peak concentration. Cmax is not itself a measure of symptom improvement, disease progression, or overall clinical benefit. Its interpretation is specific to the drug, dosing conditions, sampling schedule and study population.
The reported means describe the observed treatment-group values, while the standard deviations describe variation around those means. Neither quantity alone captures all uncertainty in the treatment contrast. The comparison estimates and confidence intervals provide additional information about the range of effect sizes compatible with the posted summary data and the recalculation approach.
The registry record names Cmax as the primary outcome and states its timeframe, but does not report the analysis population or details such as the method for deriving each participant's maximum when measurements are missing. Those details matter for reproducing the endpoint calculation, and are not reported in the registry record.
7. Results Posted in the Registry
- BIA 9-1067 25 mg: mean 716.00 versus 554.00 on control; difference 162.00 (95% CI -7.16 to 331.16), standardized effect d = 0.77; z-test p = 0.061.
- BIA 9-1067 50 mg: mean 673.00 versus 554.00 on control; difference 119.00 (95% CI -83.49 to 321.49), standardized effect d = 0.49; z-test p = 0.249.
- BIA 9-1067 100 mg: mean 570.00 versus 554.00 on control; difference 16.00 (95% CI -130.64 to 162.64), standardized effect d = 0.09; z-test p = 0.831.
Mean difference: BIA 9-1067 25 mg
95% CI: -7.16 to 331.16
Recalculated from the posted summary statistics
8. Statistical Interpretation
The posted mean Cmax values were 716.0 ng/mL for BIA 9-1067 25 mg, 673.0 ng/mL for 50 mg, 570.0 ng/mL for 100 mg, and 554.0 ng/mL for placebo. The corresponding standard deviations were 201.9, 269.9, 136.2 and 220.5 ng/mL. These are descriptive summaries; they do not by themselves establish whether observed differences are precise or attributable to treatment.
The recalculated unadjusted mean difference for 25 mg versus placebo was 162.0 ng/mL, with a 95% confidence interval from -7.156 to 331.2 and p = 0.061. For 50 mg versus placebo, the mean difference was 119.0 ng/mL, with a 95% confidence interval from -83.49 to 321.5 and p = 0.249. For 100 mg versus placebo, the mean difference was 16.0 ng/mL, with a 95% confidence interval from -130.6 to 162.6 and p = 0.831.
Each confidence interval includes zero, so the posted unadjusted calculations do not rule out no difference in mean Cmax. The intervals also include positive differences and, for each comparison, negative values. That breadth means the summary results are compatible with a range of possible contrasts, rather than identifying a narrowly determined effect. The p-values are unadjusted and should not be read as resolving uncertainty about all three dose comparisons collectively.
These contrasts were recalculated from posted summary statistics using a simple unadjusted approach. They are not presented as the trial's own crossover-model estimates. Because participants received treatments across multiple periods, a crossover analysis can account for within-participant comparisons and potentially period or sequence effects. The posted summary calculations do not make those adjustments. The registry record reports no analyses, and does not give a sponsor analysis for the primary endpoint; the interpretation therefore concerns these recalculated comparisons, not an asserted trial-model result.
The number of observations differs by condition in the posted summaries: 12 for 25 mg, 11 for 50 mg, 12 for 100 mg and 12 for placebo. The record does not explain why the 50 mg summary includes 11 observations or describe missing-data handling. The mean and standard deviation for that condition consequently summarize the reported observations without clarifying the reason for the difference.
In statistical terms, the estimates are uncertain, particularly when considered alongside their confidence intervals and the small posted group counts. The results describe levodopa Cmax in this study context. They do not establish effects on clinical outcomes or support a conclusion about treatment for Parkinson's disease.
9. Statistical Methods Explained
What is being compared? The primary endpoint is a continuous variable, levodopa Cmax in ng/mL. For each active dose, the posted comparison is its mean minus the placebo mean. A positive mean difference indicates a higher reported mean Cmax under the active-dose condition in this calculation; a negative difference would indicate a lower mean. These are unadjusted recalculations from the treatment-specific summary statistics, rather than results identified as the trial's own fitted model.
What do the means and standard deviations describe? A mean gives the arithmetic average of the observed endpoint values in a treatment condition. A standard deviation describes how spread out those values are around their mean. It is a measure of variation among observations, not a confidence interval for the mean and not a direct measure of uncertainty in the treatment contrast. For example, the reported standard deviations range from 136.2 to 269.9 ng/mL across the four conditions, showing that observations varied within conditions.
What does a confidence interval convey? A confidence interval describes uncertainty in an estimate under the assumptions of the method used. It gives a range of effect values that are reasonably compatible with the data and method; it is not a guarantee that the true effect lies in the particular interval. Here, the unadjusted intervals are calculated around the mean differences. Their inclusion of zero indicates that no difference is compatible with each interval. Their width also shows that considerable uncertainty remains about the size and direction of the contrasts.
How should the p-values be read? A p-value measures how unusual data at least as discrepant as those observed would be under a specified null model, assuming the model's conditions. It is not the probability that the null hypothesis is true, nor a measure of clinical importance. The posted p-values—0.061, 0.249 and 0.831—are unadjusted. The registry record does not report a multiplicity adjustment or a trial-specific analysis plan for these comparisons, so the values should not be treated as adjusted evidence across the set of dose comparisons.
Why does the crossover design matter? In a crossover study, participants receive different treatment conditions in separate periods. A suitable analysis can use the within-participant structure, which may account for the fact that measurements from the same participant are related. It may also consider period and sequence effects, depending on the protocol and analysis plan. General statistical practice recognizes that treating each treatment condition as if it came from an unrelated group can fail to use that pairing and can misstate uncertainty. The posted comparisons are described as simple unadjusted recalculations from summary statistics; they do not report paired estimates or a crossover model. The registry record does not report the sponsor's model or how crossover features were handled in a primary analysis.
Why can over-dispersion matter? General explanation: when observations vary more than a statistical model assumes, standard errors can be too small if the extra variation is ignored. This can make confidence intervals too narrow and p-values too small. For a continuous endpoint, the reported standard deviations offer a description of observed spread, but the record does not provide a model assessment or other evidence about whether a particular variance assumption was appropriate. No claim about over-dispersion in this study can be made from the posted summaries alone.
What information is absent? The registry record reports six outcome measures but no posted secondary results, and reports no analyses. It does not report the prespecified statistical analysis plan, the analysis population, missing-data methods, interim analyses, or the original sample-size justification. The primary outcome description identifies the endpoint and collection timeframe, but not the statistical model used for a trial-level inference. These omissions limit the ability to reproduce or fully assess the intended analysis.
The figures labelled as recalculated are deliberately narrower than a complete trial analysis: they compare posted group summaries without adjustment. They help describe the numerical contrast and its approximate uncertainty under that calculation, but should not be substituted for a crossover analysis if one was conducted outside the posted record.
10. Confidence Intervals and Precision
The mean-difference estimates are accompanied by broad confidence intervals. For BIA 9-1067 25 mg versus placebo, the estimate is 162.0 ng/mL and the interval extends from -7.156 to 331.2. For 50 mg versus placebo, the estimate is 119.0 ng/mL and the interval extends from -83.49 to 321.5. For 100 mg versus placebo, the estimate is 16.0 ng/mL and the interval extends from -130.6 to 162.6.
All three intervals include zero. Thus, under the unadjusted calculation, the intervals do not distinguish the estimated mean differences from no difference. They also encompass values in both directions, with a range of possible magnitudes. This is a statement about precision, not evidence that the treatment conditions are equivalent. Demonstrating equivalence would require an appropriate prespecified margin and analysis, neither of which is reported in the registry record.
The posted condition summaries include 11 or 12 observations, depending on treatment. Such small summaries generally provide limited precision, especially when measurements show variability. The standard deviations reported for the four conditions range from 136.2 to 269.9 ng/mL. The 50 mg condition has the largest reported standard deviation, while the 100 mg condition has the smallest. These descriptive differences in spread do not explain their cause or account for the crossover structure.
Precision also depends on the method used to calculate uncertainty. These intervals accompany unadjusted recalculations from posted summary statistics, not a reported crossover model. A paired analysis may yield different estimates of uncertainty by using within-participant relationships. Those relationships and their analysis are not reported in the registry record. The intervals should therefore be read as approximate precision for the stated unadjusted comparisons, not as definitive uncertainty estimates from the trial's intended analysis.
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.
| Effect to detect | Participants per arm, 80% power | Participants per arm, 90% power |
|---|---|---|
| 100% of the observed effect | 27 | 36 |
| 75% of the observed effect | 48 | 64 |
| 50% of the observed effect | 107 | 144 |
The sample-size figures are planning illustrations based on the observed mean differences, not the trial's original design assumptions. They are stated as participants per arm, not as total events. The calculations assume 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 original trial's sample-size justification and design assumptions are not reported in the registry record.
The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if that effect were the true one. The 90% power column gives the corresponding planning number for a 90% chance. These are prospective planning quantities, not outcomes observed in this study; this is not observed power.
For each comparison, the display considers planning for 100%, 75% and 50% of the observed effect. For 25 mg versus placebo, planning for 100% of the observed effect gives 27 participants per arm for 80% power and 36 for 90% power; planning for 75% gives 48 and 64, while planning for 50% gives 107 and 144. For 50 mg, the corresponding pairs are 67 and 90, 119 and 159, and 267 and 358. For 100 mg, they are 2,060 and 2,757, 3,662 and 4,902, and 8,238 and 11,028.
Smaller effects require more participants to detect under the same assumptions, which is why planning for a smaller fraction of the observed effect produces larger figures. These values are illustrations based on recalculated differences and a simplified two-arm framework. They do not account for the study's crossover design or establish what the original investigators planned.
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 z1−α/2 = 1.960) and the desired power (z1−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
- Observed difference Δ = 162.000; pooled standard deviation σ = 211.405.
- n = 2 × (1.96 + 0.842)2 × 211.4052 / 162.0002 = 26.7, rounded up to 27 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 <- 162 # observed difference in means
sigma <- 211.404659362087 # 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(2169453)
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 = 27 (80% power), 36 (90% power)
75% of observed effect: n per arm = 48 (80% power), 64 (90% power)
50% of observed effect: n per arm = 107 (80% power), 144 (90% power)
power.t.test: 27.7
Simulated power at n = 27 per arm: 0.787 (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 registry record gives one primary outcome, Cmax, and identifies three active-dose comparisons against placebo in the posted recalculations. The reported p-values are unadjusted. The record does not report a multiplicity strategy, such as a procedure to control the chance of false-positive findings across several comparisons. Accordingly, the p-values should be read as individual unadjusted values, not as results adjusted for considering multiple doses.
The record lists six outcome measures, but no secondary results are posted. It reports no analyses. This means the registry record does not provide a complete account of the planned or conducted inferential analyses, nor whether additional comparisons were specified. The statistical analysis plan is not reported in the registry record, so the intended hierarchy of endpoints and tests cannot be determined.
The analysis population is not reported in the registry record. The outcome description does not state whether the summaries include all randomized participants, all participants who completed treatment periods, or another defined set. The posted counts are 12 for the 25 mg condition, 11 for 50 mg, 12 for 100 mg, and 12 for placebo. The record does not explain the differing count or state whether participants with incomplete periods were included in any analysis.
Missing-data handling is also not reported in the registry record. It does not say whether endpoint measurements were unavailable, how any missing observations were treated, or whether a participant-level maximum could be calculated when some sampling times were missing. These details can affect both descriptive estimates and inferential analyses.
The registry record does not report interim analyses or stopping rules. No assumptions about interim monitoring, analysis populations, imputation, or multiplicity adjustment should therefore be inferred. These omissions do not alter the posted descriptive values, but they limit interpretation of the inferential results and the ability to reproduce the study's intended analysis.
14. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| BIA 9-1067 25 mg | 0 | 12 | 0.0% |
| BIA 9-1067 50 mg | 0 | 11 | 0.0% |
| BIA 9-1067 100 mg | 0 | 12 | 0.0% |
| Placebo | 0 | 12 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| BIA 9-1067 25 mg | 6 of 12 |
| BIA 9-1067 50 mg | 4 of 11 |
| BIA 9-1067 100 mg | 4 of 12 |
| Placebo | 5 of 12 |
Most frequent non-serious adverse event terms
| Event term | Organ system | BIA 9-1067 25 mg | BIA 9-1067 50 mg | BIA 9-1067 100 mg | Placebo |
|---|---|---|---|---|---|
| Somnolence | Nervous system disorders | 2 of 12 | 2 of 11 | 0 of 12 | 3 of 12 |
| Headache | Nervous system disorders | 2 of 12 | 0 of 11 | 1 of 12 | 3 of 12 |
| Diarrhoea | Gastrointestinal disorders | 2 of 12 | 0 of 11 | 0 of 12 | 1 of 12 |
| Nausea | Gastrointestinal disorders | 1 of 12 | 0 of 11 | 1 of 12 | 1 of 12 |
| Fatigue | General disorders | 1 of 12 | 0 of 11 | 0 of 12 | 2 of 12 |
| Impatience | Psychiatric disorders | 1 of 12 | 1 of 11 | 0 of 12 | 1 of 12 |
| Dry mouth | Gastrointestinal disorders | 1 of 12 | 0 of 11 | 0 of 12 | 1 of 12 |
| Dizziness | Nervous system disorders | 1 of 12 | 0 of 11 | 0 of 12 | 1 of 12 |
| Tremor | Nervous system disorders | 0 of 12 | 1 of 11 | 0 of 12 | 1 of 12 |
| Nightmare | Psychiatric disorders | 1 of 12 | 0 of 11 | 0 of 12 | 1 of 12 |
The serious adverse event counts are reported as zero in each treatment condition: BIA 9-1067 25 mg, 50 mg, 100 mg and placebo. The at-risk counts listed for those conditions are 12, 11, 12 and 12, respectively. The registry record lists no serious adverse event terms.
These are treatment-condition summaries in a crossover study, where participants received different conditions in separate periods. They should not be added together to infer a number of distinct participants, and the record does not give a participant-level safety analysis. The entries describe the serious adverse event reporting associated with each condition, not a comparison powered to establish safety equivalence.
Death counts are not reported in the registry record. The record also lists other adverse events affecting 6 participants in the 25 mg condition, 4 in the 50 mg condition, 4 in the 100 mg condition, and 5 in the placebo condition. Those are separate from the serious adverse event counts. The absence of reported serious events in these summaries does not establish that rare harms are absent, particularly given the study's small enrollment and short recorded study dates.
15. What the Result Does, and Does Not, Mean
The posted results describe levodopa maximum observed plasma concentration after co-administration of controlled-release levodopa/carbidopa with BIA 9-1067 at 25 mg, 50 mg or 100 mg, or with placebo. The condition means were 716.0, 673.0, 570.0 and 554.0 ng/mL, respectively. The unadjusted recalculated mean differences versus placebo were 162.0, 119.0 and 16.0 ng/mL for the three active doses, respectively.
The uncertainty intervals include zero for all three comparisons and span values on both sides of zero. The data and calculation therefore do not provide a precise estimate that rules out no difference in mean Cmax. At the same time, an interval that includes zero does not prove that there is no difference. The estimates remain uncertain, and the registry record does not report a trial-level crossover analysis that could provide a different treatment-effect estimate.
The results concern a pharmacokinetic endpoint in healthy male subjects under single-dose conditions. They do not measure symptom control, functional outcomes, disease progression, or long-term treatment. Although Parkinson's disease is listed as a condition, the registry title and summary describe healthy male participants; the record does not establish that the findings apply to people with Parkinson's disease.
Nor do these data establish equivalence between BIA 9-1067 and placebo, or establish a clinical benefit or harm. Such claims would require an appropriate design and prespecified criteria beyond the unadjusted summaries posted. The modest enrollment and incomplete reporting of analysis details further limit how far the results can be generalized. The appropriate reading is descriptive: the registry reports the observed means and recalculated contrasts, with substantial uncertainty and no posted adjusted primary analysis.
16. Why This Trial Matters Statistically
This study illustrates the distinction between a measured pharmacokinetic endpoint and a clinical outcome. Cmax summarizes the peak observed concentration of levodopa, while the trial's participant population is described as healthy male subjects. Statistical interpretation should stay within that context rather than treating concentration differences as evidence about symptoms or treatment effects in Parkinson's disease.
The crossover design is important to statistical interpretation. Participants received the different treatment conditions in separate periods, so measurements are potentially related within each participant. A paired analysis can use this structure; simple calculations based only on condition means and standard deviations do not show that relationship. The posted recalculations are therefore useful for a straightforward descriptive comparison, but they cannot replace a model that reflects the actual design.
The confidence intervals demonstrate why estimates and precision should be considered together. The active-dose mean differences vary in magnitude, but each interval includes zero and also allows effects in either direction. The point estimates alone could give an incomplete impression of what the data establish. Likewise, an unadjusted p-value should not be interpreted without considering uncertainty, multiple comparisons, and the analysis model.
The registry record also shows how reporting gaps affect reproducibility. The original sample-size rationale, statistical analysis plan, missing-data methods and analysis population are not reported. These details are central to judging whether an analysis matches the randomized crossover design and whether a planned interpretation was followed. The planning illustrations based on observed effects should not be mistaken for the trial's original design.
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 main limitation for interpreting the primary endpoint is that the posted treatment comparisons are unadjusted recalculations from summary statistics, while the study is described as a crossover trial. The record does not report a paired or crossover-model estimate, or explain whether period and sequence effects were assessed. The posted contrasts therefore do not fully represent the statistical structure implied by the design.
The enrollment was 12, and the outcome summaries include 11 observations for the 50 mg condition and 12 for each other condition. The reason for the difference and the handling of incomplete data are not reported in the registry record. The analysis population is also not reported, limiting assessment of how the posted observations relate to randomization and treatment completion.
The reported confidence intervals are wide and include zero. This limits precision for the mean differences. There are three active-dose comparisons, but no multiplicity adjustment is reported. The registry record also reports no analyses beyond the posted results, no analysis plan, and no original sample-size justification. Planning calculations based on the observed effect are illustrative and are not evidence about the design that was used.
The study concerns single-dose administration in healthy male subjects, so the endpoint and population constrain interpretation. The registry record does not provide longer-term outcomes or clinical efficacy measures. It lists Parkinson's disease as a condition but does not describe enrolled participants as having the disease. Safety summaries include no reported serious adverse events in the treatment conditions, but death counts are not reported and the record does not establish the ability to characterize uncommon events.
18. Related Tutorials
19. Related Statistical Calculators
20. Sources
- ClinicalTrials.gov: Pharmacokinetic-pharmacodynamic Interaction Between Each of Three Different Single Doses of BIA 9-1067 and a Single-dose of Controlled-release 100/25 mg Levodopa/Carbidopa — NCT02169453.
- Registry record last updated 2015-01-21; status last verified 2015-01.
- Results first posted 2015-01-21.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
21. Record Summary
NCT02169453 is a completed Phase 1 randomized, double-blind, placebo-controlled, four-way crossover study. It enrolled 12 healthy male subjects and examined single doses of BIA 9-1067 at 25 mg, 50 mg and 100 mg, each given with controlled-release levodopa/carbidopa 100/25 mg, compared with placebo given alongside levodopa/carbidopa.
The primary outcome was levodopa Cmax in ng/mL, measured from pre-dose through 72 h post-dose at specified time points. Posted means range from 554.0 ng/mL with placebo to 716.0 ng/mL with BIA 9-1067 25 mg. Recalculated unadjusted mean-difference intervals include zero for all active-dose comparisons.
The registry record does not report a trial-specific analysis model, analysis population, missing-data methods, multiplicity approach, or original sample-size rationale. These gaps limit interpretation of the recalculated comparisons, particularly given the crossover design.