The Relative Bioavailability Study of Two Ropinirole 0.25 mg Tablets Under Fed Conditions: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Relative Bioavailability Study of Two Ropinirole 0.25 mg Tablets Under Fed Conditions (NCT00830219), a randomized phase 1 study. The primary outcome is Cmax (Maximum Observed Concentration of Drug Substance in Plasma).

2. Clinical Question

This is a pharmacokinetic comparison, not a study of symptom change or clinical benefit. Its primary endpoint captures the highest measured plasma concentration over the sampling period. The reported comparison therefore describes a concentration measure in healthy adults after administration under fed conditions. The record does not establish how the observed concentration comparison translates to outcomes in people with a health condition, nor does it report a clinical outcome as the primary endpoint.

3. Trial Design

The registry record describes a completed Phase 1 randomized crossover study with no masking. It compares Teva’s ropinirole hydrochloride 0.25 mg test tablets with Requip® 0.25 mg reference tablets under fed conditions. The listed condition is healthy, and the brief description identifies healthy adult subjects. The study began and reached primary completion in 2004-11.

In general, a crossover design compares treatments across treatment periods within participants, rather than assigning each participant to just one treatment throughout. Randomization can determine the order in which treatments are received. The registry identifies the study as randomized and crossover, but the treatment sequences, period structure, washout interval, and details of how randomization was implemented are not reported in the registry record. Those details matter when assessing possible period or carryover effects, but they cannot be evaluated from the record.

The study was not masked. The record does not explain whether this refers to participants, investigators, or both, and does not describe any blinding of laboratory personnel or analysts. The registry lists 46 enrolled. For Cmax, the reported test and reference outcome groups each have a sample size of 44. The endpoint description says that all participants who completed the study had their samples analyzed. It does not say how many completed, how many were randomized, or how the posted group counts relate to the enrollment count.

The primary outcome was Cmax, with blood samples collected over a 24 hour period. The record reports three outcome measures and three analyses, but the additional outcome details and the full analysis plan are not reported in the registry record. The sponsor was Teva Pharmaceuticals USA. The record marks the study completed.

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.

First Intervention

Washout of 7 Days

Reasons for not completing this period:

Second Intervention

Analysis population for the primary outcome, as defined in the registry: All participants that completed the study had their samples analyzed.

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 Concentration of Drug Substance in Plasma), measured over Blood samples collected over a 24 hour period..

The primary endpoint is Cmax: the maximum observed concentration of drug substance in plasma. It is a continuous pharmacokinetic measure, reported in pg/mL. In this study, blood samples were collected over a 24 hour period, and the maximum observed concentration over that sampling period was used to compare the test and reference formulations.

In general, Cmax is used to describe the peak concentration reached after a dose. It can inform a comparison of the rate and extent of systemic exposure, although it is only one feature of a concentration-time profile. It does not by itself describe the full profile, total exposure, duration of exposure, or a clinical effect. Those questions require other measures or outcomes, which are not detailed in the primary endpoint description.

The registry says the study assessed bioequivalence based on Cmax and that samples from all participants who completed the study were analyzed. It reports group means and standard deviations for the outcome and also gives the sponsor’s test-to-reference geometric-mean ratio analysis. The registry record does not report the assay details, the timing of individual samples, or the criteria used to determine whether the formulations met a bioequivalence standard. Accordingly, the endpoint identifies what was measured and how it was used, but the record alone does not specify the full operational or decision rules.

7. Results Posted in the Registry

• Test (Ropinirole HCl): mean 564.09 versus 543.71 on control; difference 20.38 (95% CI -51.38 to 92.14), standardized effect d = 0.12; z-test p = 0.578.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a continuous measure, and the registry describes the reported group values as means with standard deviations. A mean describes the arithmetic average of the observations. A standard deviation describes how dispersed individual observations are around that average. It is not a confidence interval for the mean and does not directly give the precision of the treatment comparison.

What does the recalculated mean difference represent?

The recalculated comparison subtracts the posted reference mean from the posted test mean. It is a simple, unadjusted comparison based on the summary statistics. Its estimate is 20.38 pg/mL, and its 95% confidence interval extends from -51.38 to 92.14 pg/mL. The interval gives a range of values compatible with the data under the assumptions of that calculation. Since zero lies within the interval, the data do not rule out no arithmetic mean difference at the confidence level used for this recalculation.

This recalculation is not the same as a crossover analysis that uses participant-level paired measurements. In general, a crossover analysis can account for the fact that observations from the same participant are related. The registry identifies a crossover design but does not report enough information about its statistical method to determine whether or how the sponsor accounted for pairing, period, or sequence. The unadjusted recalculation should therefore be read as a summary-statistic comparison, not as a reconstruction of the sponsor’s full analysis.

How does the sponsor’s ratio analysis differ?

The sponsor reported the ratio of the test-to-reference geometric means multiplied by 100. Its estimate is 103.53, with a 90% confidence interval from 99.16 to 108.09. A geometric mean is based on a multiplicative scale and is often used when concentration data are analyzed after a logarithmic transformation. In general, a ratio compares relative rather than absolute levels. The registry does not state the sponsor’s calculation method, transformation, model, or handling of the crossover structure, so those details cannot be confirmed from the record.

The arithmetic mean difference and geometric-mean ratio answer different statistical questions and use different scales. A difference is expressed in the original units, pg/mL; a ratio expresses the test result relative to the reference result. The confidence intervals also differ in level: the recalculation gives a 95% interval, while the sponsor reports a 90% interval. They should not be compared as if they were estimates from the same method or endpoint scale.

What does a confidence interval communicate?

In general, a confidence interval describes the uncertainty around an estimate under a specified statistical procedure. A narrower interval indicates greater precision for that estimate under that procedure; a wider interval indicates greater uncertainty. The interval does not show the distribution of individual participant values, and it is not a guarantee that the true value lies inside the particular interval. Interpretation also depends on the model and assumptions used to calculate it.

For the recalculated difference, the interval spans values below and above zero. For the sponsor’s ratio, the reported interval gives a range on the ratio scale. To assess equivalence, the ratio interval must be compared with appropriate prespecified bounds. The bounds are not reported in the registry record. Without them, the ratio and interval can be described, but a formal equivalence determination cannot be independently verified.

Why can the analysis scale matter?

Concentration measures may have a skewed distribution, and statistical methods can use a logarithmic scale to model multiplicative variation. In general, using a geometric mean and a ratio can be suitable for relative comparisons when the analysis assumptions support that approach. However, the record does not give distributional diagnostics or details of the sponsor’s model. The posted arithmetic summaries and sponsor’s geometric comparison therefore provide distinct views of the data, rather than enough information to reproduce the complete analysis.

In general, over-dispersion means that variability is greater than a model expects. If present and ignored, it can make uncertainty estimates unreliable. The registry does not report a dispersion assessment or describe an over-dispersion adjustment, so no conclusion about that issue can be drawn for this study. More generally, conclusions about precision depend on the analysis model, the crossover correlation structure, and the available observations, not just the group means and standard deviations.

The registry reports three analyses, but the methods for the sponsor’s analysis are not specified. It also does not report a statistical analysis plan, a handling strategy for missing observations, or details of any sensitivity analyses. These omissions restrict how fully the sponsor’s result can be reproduced or checked. The posted means, standard deviations, confidence intervals, and p-value still permit a descriptive reading, provided the recalculated and sponsor-reported analyses are kept distinct.

10. Confidence Intervals and Precision

The recalculated arithmetic mean difference is 20.38 pg/mL, with a 95% confidence interval from -51.38 to 92.14 pg/mL. The interval is broad enough to include both a negative difference and a positive difference. This means that the unadjusted estimate is not highly precise about the direction or magnitude of the arithmetic mean difference. Its width reflects uncertainty under the assumptions of the recalculation; it should not be treated as a range of individual Cmax values.

The sponsor reported a geometric-mean ratio multiplied by 100 of 103.53, with a 90% confidence interval from 99.16 to 108.09. This interval is on a relative scale and has a different confidence level from the recalculated difference interval. It describes uncertainty around the sponsor’s ratio estimate as reported, but the sponsor’s method is not specified. The ratio interval cannot be used to infer the width or location of the arithmetic mean difference interval.

Precision and equivalence are related but separate considerations. A confidence interval conveys uncertainty; an equivalence decision also requires prespecified bounds. The bounds are not reported in the registry record. Thus, the sponsor’s interval can be described, but the record does not make it possible to check the interval against the decision criteria. The registry also does not report the original statistical assumptions or the detailed crossover model, which would be relevant when judging how accurately uncertainty was estimated.

The posted standard deviations, 174.5 pg/mL for the test formulation and 168.9 pg/mL for the reference formulation, describe variation in the reported groups. They do not replace the confidence intervals for the comparison. The group sample sizes are reported as 44 for each formulation, but the record does not supply participant-level data needed to reproduce a paired crossover estimate.

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, not total events. They are illustrations based on the observed effect, not the trial’s own design calculations. The planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is set at the stated fraction of the observed effect. The original design assumptions for this trial are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for an analysis to have an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the assumptions were correct. The 90% power column gives the corresponding illustrative number per arm for a 90% chance. These are planning concepts, not guarantees about a future study’s result. The calculations use the observed effect as their starting point, so they should not be read as evidence about the adequacy of the actual trial’s design.

The rows consider planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For 100% of the observed effect, the figures are 1,115 participants per arm for 80% power and 1,493 for 90% power. For 75% of the observed effect, they are 1,982 and 2,653. For 50% of the observed effect, they are 4,459 and 5,970. Smaller effects need more participants to detect under the same assumptions, which is why the illustrative requirements rise as the target effect becomes smaller.

This is not observed power. The figures are hypothetical sample-size illustrations, not a retrospective measure of how likely the completed trial was to produce a significant result.

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 = 20.380; pooled standard deviation σ = 171.738.
2. n = 2 × (1.96 + 0.842)² × 171.738² / 20.380² = 1,114.7, rounded up to 1,115 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 <- 20.38                      # observed difference in means
sigma <- 171.73807222046                     # 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(830219)
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 = 1,115 (80% power), 1,493 (90% power)
 75% of observed effect: n per arm = 1,982 (80% power), 2,653 (90% power)
 50% of observed effect: n per arm = 4,459 (80% power), 5,970 (90% power)
power.t.test: 1115.7 
Simulated power at n = 1,115 per arm: 0.803 (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. Analyses Reported by the Sponsor

The sponsor’s posted analysis reports the test-to-reference geometric-mean ratio multiplied by 100 as 103.53, with a 90% confidence interval from 99.16 to 108.09. The registry classifies this as a non-inferiority or equivalence analysis. No p-value, method, or decision bounds are reported for that analysis.

The recalculation uses the posted arithmetic means and standard deviations to estimate an unadjusted mean difference of 20.38 pg/mL, with a 95% confidence interval from -51.38 to 92.14 and p = 0.578. It is a simple check from summary statistics, not a replication of the sponsor’s geometric-mean analysis or a reconstruction of a crossover model. The two estimates use different scales and confidence levels, so their numerical results should not be compared as though they were directly interchangeable.

The sponsor’s analysis is the trial’s own reported ratio analysis. The recalculation can help describe the posted arithmetic summaries, but it does not replace the sponsor’s analysis. Because the sponsor’s method and equivalence limits are not reported in the registry record, the ratio result cannot be independently assessed against a stated decision rule. The record does not report enough information to determine how the two analytical approaches were reconciled.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures and three analyses, while identifying Cmax as the primary outcome. It reports no secondary outcomes as posted. The descriptions and results for the other outcome measures are not available in the record summarized for this analysis. Their relationship to the primary question therefore cannot be assessed.

Multiplicity arises when several outcomes or statistical comparisons are considered. In general, testing more than one hypothesis can increase the chance of at least one apparently notable result if no adjustment or prespecified hierarchy is used. Whether that issue applies, and how it was handled, depends on the analysis plan. A multiplicity strategy is not reported in the registry record. It is not possible to determine whether the three analyses represent separate hypotheses, different summaries of outcomes, or another arrangement.

The primary endpoint description says that all participants who completed the study had their samples analyzed. The record lists 46 participants enrolled and reports 44 in each primary outcome group. It does not state how many completed the study, how participants were assigned to analysis populations, whether any observations were missing, or how missing data were handled. The posted counts should not be used to infer the number or reasons for any missing observations.

The registry does not describe an intention-to-treat, per-protocol, pharmacokinetic, or other named analysis population. It gives no participant-level flow or account of exclusions. The phrase about completed participants having samples analyzed describes the endpoint population in general terms, but does not supply enough detail to reproduce the inclusion rules.

The statistical analysis plan, protocol-level analysis details, interim analyses, and sensitivity analyses are not reported in the registry record. The absence of these details does not establish that a method was or was not used; it means that the method cannot be evaluated from this record. In particular, the crossover model, treatment-period handling, sequence effects, and any approach to missing measurements are not specified.

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

The result describes a comparison of Cmax for two ropinirole 0.25 mg tablet formulations under fed conditions in healthy adults. The posted arithmetic means are 564.1 pg/mL for the test formulation and 543.7 pg/mL for the reference formulation. The sponsor reported a test-to-reference geometric-mean ratio multiplied by 100 of 103.53, with a 90% confidence interval from 99.16 to 108.09. These are pharmacokinetic summaries from the study, not direct measures of a clinical outcome.

The recalculated arithmetic difference has a 95% confidence interval from -51.38 to 92.14 pg/mL and an unadjusted p-value of 0.578. This shows that the simple unadjusted comparison does not precisely determine the direction or size of an arithmetic mean difference. It is not an equivalence test. A p-value above a conventional significance threshold does not prove that two formulations are equivalent or identical.

The sponsor’s result is explicitly classified as a non-inferiority or equivalence analysis, but its method and decision bounds are not reported. Without those bounds, the reported ratio interval cannot establish whether a formal equivalence criterion was satisfied. The result also cannot establish equivalence for endpoints not reported, for different conditions of administration, or for clinical outcomes.

The study was conducted in healthy adult subjects and assessed concentration under fed conditions. It does not directly answer questions about people with a health condition, clinical response, or longer-term outcomes. The registry record also does not report detailed safety results, so this comparison should not be read as a comprehensive assessment of safety.

In short, the record contains a sponsor-reported relative Cmax analysis and a separate unadjusted recalculation from the posted group summaries. Each has a defined but limited interpretation. The record supports describing the estimates and their uncertainty; the available information does not support claims beyond the population, conditions, endpoint, and analysis details recorded.

16. Why This Trial Matters Statistically

This study illustrates why the analysis scale matters in clinical biostatistics. The same endpoint can be described through arithmetic means and an absolute difference, or through geometric means and a relative ratio. Those summaries answer different questions, use different scales, and can produce confidence intervals that are not directly comparable. Keeping the sponsor’s ratio result separate from a simple recalculation of the arithmetic summaries avoids treating unlike estimates as if they were duplicates.

It also highlights the distinction between testing for a difference and assessing equivalence. The recalculated p-value and interval concern an unadjusted arithmetic mean difference. The sponsor’s reported analysis is classified as non-inferiority or equivalence and uses a geometric-mean ratio. Equivalence requires an explicit decision rule, including bounds. Since those bounds and the sponsor’s method are not reported, the ratio result can be described but cannot be independently checked against a stated criterion.

The crossover design is statistically relevant because, in general, observations from the same participant can be related across treatments. A participant-level paired analysis can use that relationship, while a simple comparison of group summaries may not. The registry identifies a randomized crossover design but does not provide the details needed to determine how the reported analysis handled pairing, periods, or sequences. This makes transparent reporting of the model and analysis population important for interpretation.

Finally, the record separates what is observed from what is planned. The sample-size illustrations use the observed effect and stated planning assumptions; they are not observed power and do not establish the original design rationale. Together, these features make the study a useful example of reading pharmacokinetic comparisons cautiously: identify the endpoint and estimand, distinguish analysis methods, inspect uncertainty, and note what the registry does not report.

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 population is limited to healthy adult subjects, and the comparison was conducted under fed conditions. The registry record does not report results in a clinical population or comparisons under other administration conditions. The primary endpoint is a concentration measure rather than a clinical outcome, so the result does not directly describe clinical effects.

The study was unmasked. The record does not specify who was unmasked or whether laboratory staff and analysts were blinded. The crossover design is identified, but treatment sequence, period details, washout interval, and handling of possible period or carryover effects are not reported in the registry record. These omissions make it difficult to assess the design and analysis in detail.

The sponsor’s analysis method and equivalence bounds are not reported. Consequently, the ratio estimate and its 90% confidence interval cannot be independently compared with the decision criteria used for the study. The recalculation is unadjusted and based on posted summary statistics; it does not reproduce a participant-level crossover analysis. The record does not provide participant-level data or enough model details to do so.

The registry lists 46 enrolled and reports 44 participants in each primary outcome group, but does not explain the relationship between those counts or describe participant flow. It says samples from all participants who completed the study were analyzed, while not stating how many completed or how missing measurements were handled. The outcome and analysis descriptions beyond the primary endpoint are not reported in the registry record. Detailed safety results and the statistical analysis plan are also not reported.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: The Relative Bioavailability Study of Two Ropinirole 0.25 mg Tablets Under Fed Conditions — NCT00830219.
• Registry record last updated 2009-09-15; status last verified 2009-09.
• Results first posted 2009-08-18.
• 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

The registry record describes a completed, randomized, unmasked Phase 1 crossover study sponsored by Teva Pharmaceuticals USA. It compared ropinirole hydrochloride 0.25 mg test tablets with Requip® 0.25 mg reference tablets under fed conditions in healthy adults. The study began and reached primary completion in 2004-11, and 46 participants were enrolled.

The primary endpoint was Cmax, maximum observed plasma concentration, measured from blood samples collected over a 24 hour period. The posted arithmetic means were 564.1 pg/mL for the test formulation and 543.7 pg/mL for the reference formulation. The sponsor reported a geometric-mean ratio multiplied by 100 of 103.53, with a 90% confidence interval from 99.16 to 108.09. The registry does not report the sponsor’s method or decision bounds. The record also does not provide detailed crossover procedures, missing-data handling, or the full statistical analysis plan.