Terbinafine HCl 250 mg Tablet Formulations Under Non-Fasting Conditions: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Terbinafine HCl 250 mg Tablet Formulations Under Non-Fasting Conditions (NCT00833664), a randomized phase 1 study. The primary outcome is Cmax - Maximum Observed Concentration - Terbinafine in Plasma.

2. Clinical Question

This is a formulation-comparison question, not a comparison between terbinafine and no treatment. The crossover design means that the two formulations were given in different periods, with the order reversed between the two treatment sequences. The record does not state the duration between periods or the procedures used to account for period or sequence effects. It also does not report an equivalence margin or a formal decision rule for interpreting the bioequivalence assessment. Therefore, the posted estimates can be described, but the registry record alone does not establish which formal criterion the investigators intended to apply.

3. Trial Design

This was a Phase 1, randomized, unmasked, crossover study of two 250 mg tablet formulations: test terbinafine HCl and reference Lamisil®. The study title specifies non-fasting conditions, and the study summary describes administration under post-prandial conditions. The population was healthy adult male and female participants who did not use tobacco.

The two treatment sequences reversed the order of the formulations. One sequence received the test formulation in the first period and Lamisil® in the second; the other received Lamisil® first and the test formulation second. Thus, the intended comparison was between formulations administered to participants across separate periods, rather than between parallel groups receiving only one formulation. The registry record does not report the period duration, washout interval, dose timing details, or the procedures used to assess period, sequence, or carryover effects.

The recorded enrollment was 22. The primary endpoint analysis included data from subjects who completed the study; the posted group summaries each contain 21 participants. The registry lists the study as completed, with start and primary-completion dates both recorded as 2002-01.

The primary outcome was Cmax, maximum observed concentration of terbinafine in plasma, measured in ng/mL from blood samples collected over a 144 hour period. The registry also lists 3 outcome measures and 3 analyses, but the details of additional outcomes are not posted in the record. The trial’s original sample-size justification, planned statistical model, missing-data procedures, and any interim analyses 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.

First Intervention

Washout: 14 Days

Second Intervention

Analysis population for the primary outcome, as defined in the registry: Data from all subjects who completed the study were included in the statistical analysis.

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 - Terbinafine in Plasma, measured over Blood samples collected over144 hour period.

The primary endpoint was Cmax, the maximum observed concentration of terbinafine in plasma, measured in ng/mL. It represents the highest concentration observed among the blood samples collected over a 144 hour period. The registry identifies bioequivalence based on Cmax as the endpoint’s purpose.

For a formulation comparison, Cmax is one way to describe the peak exposure observed after dosing. Comparing the test and reference formulations on this measure can help characterize whether their observed peak concentrations are similar under the study conditions. The registry reports the endpoint as a mean with standard deviation for each formulation, and separately gives a test-to-reference ratio of least-squares means.

These summaries are not interchangeable. A difference between arithmetic means describes the absolute separation in ng/mL, while a ratio expresses one formulation’s estimated value relative to the other. A bioequivalence conclusion also depends on the analysis method and the acceptance criteria specified for the study. The acceptance margin and full decision rule are not reported in the registry record, so the endpoint description alone is not enough to determine how the investigators would classify the result against a prespecified criterion.

The record says that blood samples were collected over 144 hour, but does not provide the sampling schedule or explain how concentrations below assay limits, if any, were handled. Assay details and the exact calculation procedure for Cmax are not reported in the registry record.

7. Results Posted in the Registry

• Lamisil®: mean 971.00 versus 906.00 on control; difference 65.00 (95% CI -132.07 to 262.07), standardized effect d = 0.20; z-test p = 0.518.

8. Statistical Interpretation

9. Statistical Methods Explained

The results include two statistical descriptions of the formulation comparison: a recalculated unadjusted difference between the posted means and the registry’s reported test-to-reference ratio of least-squares means. These answer related but distinct questions. The mean difference is in the original concentration units, ng/mL. The ratio expresses the test estimate relative to the reference estimate. The registry does not report enough methodological detail to reconstruct the sponsor’s least-squares analysis.

What does a mean and standard deviation describe?

A mean describes the average observed Cmax in the analyzed group. The standard deviation describes how spread out individual observations were around that group mean. The posted values are 906.0 with standard deviation 196.0 for the test formulation and 971.0 with standard deviation 417.0 for Lamisil®. These descriptive summaries do not show the paired differences for individual participants. In a crossover study, the within-participant pattern can be important because each participant may have observations under both formulations.

What is the unadjusted mean difference?

The recalculated comparison is Lamisil® minus the test formulation. Its estimate is 65.0 ng/mL. A value of zero would represent no difference between the two arithmetic means under that comparison’s definition. The 95% confidence interval is -132.1 to 262.1. This is a simple, unadjusted recalculation from the posted summaries, not the reported least-squares analysis. It does not account for a crossover model’s within-participant structure. The registry’s discrepancy flag is false, so there is no identified discrepancy between the posted summary values and this recalculation; the sponsor’s own analysis remains the relevant reported analysis.

What does the p-value describe?

The unadjusted p-value is 0.518. In general, a p-value measures how surprising results at least as incompatible with a specified null model would be if that model and the calculation assumptions were correct. It does not measure the probability that the null hypothesis is true, nor does it establish equivalence. This p-value belongs to the unadjusted mean comparison and should not be attributed to the sponsor’s ratio analysis, for which no p-value is reported.

What does the ratio represent?

The reported test-to-reference ratio of least-squares means is 98.2, with a 90% confidence interval from 88.1 to 109.5. In general, a ratio compares an estimated value for one formulation with an estimated value for the other, expressed on a relative scale. Least-squares means usually arise from a statistical model, but the model details are not reported in the registry record. The record also does not specify whether the ratio was calculated on a transformed scale or how it was converted to the displayed scale. Therefore, interpretation should stay with the stated quantity and interval rather than assume unreported modeling details.

Why is a crossover analysis distinctive?

In general, a crossover design allows comparisons within the same participant, which can reduce the impact of stable differences between participants when the analysis accounts for the repeated measurements. Valid interpretation also depends on design and analysis details, including handling of period and sequence effects and any possible carryover. The registry reports randomized treatment order but does not report the statistical model, washout details, or the handling of these effects. The simple unadjusted recalculation from group summaries cannot recover participant-level pairing or substitute for a fully described crossover analysis.

How should bioequivalence be assessed?

In general, a bioequivalence assessment compares an estimated formulation relationship with prespecified acceptance limits and considers the uncertainty around that estimate. The registry describes Cmax as an endpoint for bioequivalence, and reports a 90% interval for the ratio. However, the acceptance limits, prespecified decision rule, and analysis method are not reported in the registry record. It is therefore possible to describe the ratio and its interval, but not to determine from this record whether the sponsor’s formal criterion was met.

The registry lists 3 outcome measures and 3 analyses, but only the primary endpoint analysis is characterized in the registry entries. The full statistical analysis plan, including transformations, covariate adjustment, treatment of outliers, multiplicity handling, and interim analyses, is not reported in the registry record.

10. Confidence Intervals and Precision

A confidence interval describes uncertainty around an estimated quantity under the assumptions of the analysis. It gives a range of values that are reasonably compatible with the observed data and the specified method. It is not a guarantee that the true value lies in the interval, nor does it state the probability that a particular value is correct.

For the unadjusted difference in means, the 95% confidence interval runs from -132.1 to 262.1 ng/mL around the estimate of 65.0 ng/mL. The interval includes zero and also includes values in either direction. Its span indicates that this recalculation does not estimate the difference with high precision. The limits should be interpreted as uncertainty for the unadjusted mean difference, not as an interval for the sponsor’s ratio analysis.

The registry-reported ratio is 98.2, with a 90% confidence interval from 88.1 to 109.5. This interval describes uncertainty on the reported ratio scale. It should not be compared with an assumed bioequivalence range, because the registry record does not state the acceptance limits. Its 90% level also differs from the 95% interval for the unadjusted difference; these intervals arise from different reported quantities and should not be compared as if they were the same analysis.

In general, interval width depends on the amount of information and the variability of the data, as well as the method used. The posted standard deviations differ between the formulation summaries, and the sample sizes are 21 in each. The crossover pairing could affect the precision of a within-participant analysis, but the registry record does not report the participant-level covariance or the sponsor’s model details. The uncertainty reported for the recalculation therefore should not be taken as a complete description of the precision of the sponsor’s 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.

The planning figures are participants per arm, not total event counts. They are illustrations based on the observed effect and are not the trial’s original sample-size calculation. 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 the stated fraction of the observed effect. The trial’s own original design assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for an analysis with an 80% chance of detecting the specified effect, under the listed assumptions, if that effect is the true one and the model assumptions hold. The 90% power column gives the corresponding planning number for a 90% chance. These are planning concepts, not guarantees about a future study’s result. The figures are based on the observed effect in this trial and are not observed power.

The rows consider planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For the full observed effect, the figures are 395 participants per arm for 80% power and 528 participants per arm for 90% power. For 75% of the observed effect, they are 702 and 939 participants per arm, respectively. For 50% of the observed effect, they are 1,578 and 2,112 participants per arm, respectively.

The pattern illustrates a general principle: smaller effects are harder to distinguish from random variation, so detecting them with the same power generally requires more participants. These calculations use a two-arm equal-allocation planning framework and normal approximation. They are not a reconstruction of the crossover trial’s design, and the registry record does not report the original sample-size justification or its assumptions.

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 = 65.000; pooled standard deviation σ = 325.811.
2. n = 2 × (1.96 + 0.842)² × 325.811² / 65.000² = 394.4, rounded up to 395 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 <- 65                      # observed difference in means
sigma <- 325.810527761151                     # 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(833664)
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 = 395 (80% power), 528 (90% power)
 75% of observed effect: n per arm = 702 (80% power), 939 (90% power)
 50% of observed effect: n per arm = 1,578 (80% power), 2,112 (90% power)
power.t.test: 395.4 
Simulated power at n = 395 per arm: 0.805 (20000 replicates)

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

13. Analyses Reported by the Sponsor

The registry’s own reported analysis is the test-to-reference ratio of least-squares means: 98.2, with a 90% confidence interval from 88.1 to 109.5. It is the sponsor-reported result in the registry record. The method used to calculate the least-squares means is not reported, and the record does not give a p-value or the acceptance limits for the bioequivalence assessment.

The recalculated result is a simple unadjusted difference between the posted arithmetic means: 65.0 ng/mL for Lamisil® minus the test formulation, with a 95% confidence interval from -132.1 to 262.1 and an unadjusted p-value of 0.518. It uses a different scale and a different comparison from the reported ratio. It should not be used as a substitute for the sponsor’s analysis, particularly because the study used a crossover design and the recalculation cannot represent participant-level pairing.

The discrepancy flag is false, so the posted summaries do not identify a conflict requiring the recalculation to override the reported result. The sponsor’s own analysis takes precedence for describing the registry’s reported analysis. This does not resolve whether a formal bioequivalence criterion was met: the acceptance limits and the sponsor’s decision rule are not reported in the registry record.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 3 analyses, but the available details identify the primary outcome as Cmax and do not characterize the other outcomes or their analyses. The number of secondary outcomes posted is 0. The outcome hierarchy beyond the primary endpoint, the set of hypotheses tested, and any procedures for controlling multiplicity are not reported in the registry record.

Multiplicity matters when several outcomes, time points, or comparisons are analyzed. In general, examining more than one result can increase the chance of finding an apparently notable result by chance if no adjustment or prespecified hierarchy is used. The record does not establish whether multiplicity adjustment was planned, whether the primary endpoint was the only confirmatory test, or how results across analyses were to be interpreted. No adjustment should be assumed.

The primary analysis population is described as all subjects who completed the study. The posted summaries contain 21 participants for each formulation, while enrollment was 22. The record does not describe the disposition of the participant who is not represented in those summaries, the reason for non-inclusion, or whether any endpoint data were missing. It also does not report imputation, exclusion, or sensitivity-analysis procedures.

In general, missing data can affect both the size and interpretation of an estimate, particularly if the reasons for missingness are related to treatment or outcome. Here, the record does not provide enough information to assess that possibility. The crossover design also makes the availability of measurements from both periods relevant, but completion and analysis details by sequence are not reported.

The registry does not report an interim-analysis plan, stopping rules, or a detailed statistical analysis plan. These omissions mean that the posted primary result can be described, but the handling of multiple analyses and incomplete data cannot be fully evaluated from the registry record.

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

The results describe the observed Cmax values for test terbinafine HCl 250 mg tablets and reference Lamisil® 250 mg tablets in healthy adult participants under non-fasting, post-prandial conditions. The posted means were 906.0 ng/mL for the test formulation and 971.0 ng/mL for the reference, with 21 participants in each summary. The recalculated unadjusted difference and its confidence interval describe uncertainty about the difference between those means.

The registry also reports a test-to-reference ratio of least-squares means of 98.2, with a 90% confidence interval from 88.1 to 109.5. This is the reported ratio analysis, not the same quantity as the unadjusted mean difference. The registry describes Cmax as an endpoint for bioequivalence, but it does not report the acceptance limits or full analysis method. The reported estimate and interval alone therefore do not establish whether a formal bioequivalence criterion was met.

The result concerns one pharmacokinetic endpoint and two tablet formulations in the study population and conditions. It does not establish comparative effects on symptoms, disease outcomes, safety, or other clinical outcomes; these are not characterized in the posted primary result. The registry does not report results for secondary outcomes. Nor do these results establish how the formulations compare in populations or conditions not studied.

The study was randomized and crossover, but unmasked. The record reports treatment sequence and the primary analysis population but does not provide sufficient detail about period effects, carryover, missing data, or the model used for the sponsor’s ratio. Those limits matter when judging how completely the reported estimates reflect the intended within-participant comparison.

Statistically, the appropriate reading is descriptive and bounded by the reported uncertainty. The unadjusted interval spans zero, and the sponsor-reported ratio has its own 90% interval. Neither should be converted into a categorical claim about equivalence without the prespecified criterion and analysis details, which are not reported in the registry record.

16. Why This Trial Matters Statistically

This trial is statistically useful as an example of how the same formulation comparison can be expressed in different ways. The unadjusted arithmetic mean difference is measured in ng/mL, while the registry’s reported result is a test-to-reference ratio of least-squares means. Each has a different interpretation, and the ratio analysis cannot be reconstructed from the group means and standard deviations alone.

The crossover design also highlights why participant-level structure matters. When participants receive both formulations in separate periods, the relationship between their measurements can contribute to the precision of the comparison. Group-level summaries do not retain that pairing. A simple recalculation can be informative as a transparent description of the posted means, but it cannot replace the analysis of a crossover study.

Precision is central to interpreting formulation comparisons. The unadjusted mean difference has a 95% confidence interval from -132.1 to 262.1, while the reported ratio has a 90% confidence interval from 88.1 to 109.5. These intervals refer to different estimands, and a formal bioequivalence judgment additionally requires acceptance limits. Their absence from the registry record illustrates why an estimate should not be interpreted in isolation from the prespecified decision framework.

Finally, the planning illustrations show that power calculations depend on the effect one seeks to detect. Smaller target effects require more participants under the stated assumptions. These are not the trial’s original design calculations, and they are not observed power. Separating planning illustrations from the trial’s own design helps avoid treating a retrospective calculation as evidence of the original rationale or of the result’s certainty.

17. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives limited detail about the design and conduct beyond randomization, unmasked treatment, and the two crossover sequences. The washout interval, period duration, dose timing, and procedures for evaluating period, sequence, or carryover effects are not reported. Those details are relevant to interpreting a crossover comparison but cannot be inferred from the posted results.

The record does not describe the sponsor’s statistical model for the least-squares means, the calculation scale for the ratio, or the method used to construct its 90% confidence interval. It also does not report the acceptance limits or decision rule for bioequivalence. Consequently, the reported ratio can be quoted and described, but a formal classification against the study’s intended criterion cannot be verified from the registry record.

Enrollment was 22, while the primary analysis summaries include 21 participants per formulation. The record says the analysis included subjects who completed the study, but does not give participant flow, the reason for any non-inclusion, or details about missing measurements. The available record therefore does not permit assessment of how incomplete participation may have influenced the estimates.

The study was unmasked and involved healthy adults who did not use tobacco. The findings are specific to the formulations, population, and non-fasting, post-prandial conditions described; the record does not establish applicability to other settings or populations. Details of assay procedures, sampling times within the 144 hour collection period, and handling of values below assay limits are not reported. The trial’s original sample-size justification, detailed analysis plan, and interim-analysis procedures are also not reported in the registry record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Terbinafine HCl 250 mg Tablet Formulations Under Non-Fasting Conditions — NCT00833664.
• Registry record last updated 2023-05-30; status last verified 2023-05.
• 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

This completed Phase 1 study randomized 22 healthy adult participants to one of two treatment sequences in an unmasked crossover comparison of test terbinafine HCl 250 mg tablets and reference Lamisil® 250 mg tablets. The study concerned non-fasting, post-prandial administration. The primary endpoint was Cmax, maximum observed terbinafine concentration in plasma, measured in ng/mL from blood samples collected over a 144 hour period.

The primary analysis included subjects who completed the study, and each posted formulation summary contains 21 participants. The registry reports a test-to-reference ratio of least-squares means of 98.2 with a 90% confidence interval from 88.1 to 109.5. An unadjusted recalculation of the posted means gives a difference of 65.0 ng/mL, with a 95% confidence interval from -132.1 to 262.1 and p-value of 0.518.

The registry record does not report the bioequivalence acceptance limits, detailed analysis model, original sample-size justification, or procedures for missing data and multiplicity. The posted estimates can be interpreted descriptively, but the formal bioequivalence decision framework is not available in the record.