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

1. Trial at a Glance

This page covers the registry results for Terbinafine HCl 250 mg Tablet Under Fasting Conditions (NCT00833586), a randomized phase 1 study. The primary outcome is Cmax - Maximum Observed Concentration - Terbinafine in Plasma.

2. Clinical Question

In practical statistical terms, the comparison asks how the observed peak plasma concentrations following the test formulation relate to those following the reference formulation in this fasting study. The crossover arrangement means that the same participant was scheduled to receive both formulations, although the registry does not report the statistical model used to account for the repeated measurements. The posted sponsor result expresses the comparison as a test-to-reference ratio of least-squares means multiplied by 100. A separate unadjusted recalculation gives an absolute mean difference based on the posted arm summaries. These summaries answer related but distinct statistical questions, so their estimates and intervals should not be treated as interchangeable.

3. Trial Design

This was a Phase 1, randomized, unmasked, crossover study sponsored by Teva Pharmaceuticals USA. It was listed as completed, with enrollment of 28. The registry lists the start and primary completion as 2002-01. The study was conducted under fasting conditions in healthy adult male and female participants who did not use tobacco.

The two formulations were Terbinafine HCl 250 mg tablets, identified as the test treatment, and Lamisil® 250 mg tablets, identified as the reference treatment. The crossover sequences were described explicitly: one sequence received the test in the first period and the reference in the second, while the other received the reference first and the test second. Randomization assigned participants to the sequences. Because each sequence included both formulations, the design differs from a parallel-group trial in which each participant receives only one treatment.

The registry does not report the randomization procedure, the duration of either period, a washout interval, or the timing of treatment administration beyond the fasting condition. It also does not report masking, which is listed as none, or details about the conduct of the study beyond the recorded design features. The primary endpoint was Cmax, assessed using blood samples collected over a 144 hour period. The primary analysis population is described as all subjects who completed the study. The number completing the study and any withdrawals or exclusions are not reported in the registry record, although the posted arm summaries list 28 participants for each formulation.

As a crossover study, the design can support a within-participant comparison, but interpretation depends on how the analysis accounts for the paired observations and period or sequence effects. The registry does not report those analytical details. The reported sponsor result uses a ratio of least-squares means, whereas the unadjusted recalculation compares the arm-level means. The distinction matters because a crossover analysis may use information about the within-participant relationship that is not available from the reported arm-level summaries.

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 over 144 hour period.

Cmax is the maximum observed concentration of terbinafine in plasma after administration of a formulation. It is a continuous pharmacokinetic measure, expressed in ng/mL. The registry describes the endpoint as “Cmax - Maximum Observed Concentration - Terbinafine in Plasma” and identifies bioequivalence as based on Cmax. Blood samples were collected over a 144 hour period.

As a general statistical concept, Cmax provides a summary of the highest measured plasma concentration during the sampling period. Comparing the test and reference formulations on this measure can describe whether their observed peak concentrations are similar, while a ratio expresses the test result relative to the reference result. Cmax is only one feature of a concentration-time profile; by itself, it does not describe the entire profile or establish what happens for other outcomes.

The registry reports arm-level means and standard deviations for Cmax, as well as a sponsor analysis on the test-to-reference ratio scale. It does not report the full concentration-time data, the detailed endpoint derivation rules, or the formal bioequivalence margins and decision procedure. The word “bioequivalence” appears in the endpoint description, but the numerical criteria used to make that determination are not reported in the registry record. Therefore the posted estimates can be described statistically, but the registry record alone does not establish which prespecified acceptance rule was applied.

7. Results Posted in the Registry

• Lamisil®: mean 873.20 versus 840.20 on control; difference 33.00 (95% CI -126.82 to 192.82), standardized effect d = 0.11; z-test p = 0.686.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies Cmax as a continuous endpoint and reports means with standard deviations for the two formulations. It also lists a sponsor analysis of the test-to-reference ratio of least-squares means multiplied by 100. The specific method used for that analysis is not reported in the registry record. The distinction between the descriptive summaries, the recalculated comparison, and the sponsor’s own analysis is important because each conveys a different part of the evidence.

What does the mean describe?

A mean is a measure of the central location of a set of observations. For Cmax, it summarizes the average measured peak concentration among the participants included in the arm summary. The reported means are 840.2 ng/mL for Terbinafine and 873.2 ng/mL for Lamisil®. A mean alone does not show how individual values are distributed around it, so the standard deviation is also reported. The standard deviations, 310.8 and 299.3, describe the spread of the observed values around their respective means.

These arm summaries are descriptive. In a randomized crossover study, the treatment observations are linked within participants rather than being independent groups in the usual parallel-group sense. A summary for each formulation does not show whether participants with higher values on one formulation also tended to have higher values on the other. That within-participant relationship can affect the uncertainty of a paired treatment comparison.

What is the unadjusted recalculation?

The recalculated estimate is a simple unadjusted mean difference based on the posted summary statistics. It is 33.0 ng/mL for Lamisil® relative to Terbinafine, with an interval from -126.8 to 192.8 and an unadjusted p-value of 0.686. The difference scale expresses the comparison in the original measurement unit, ng/mL. It asks how far apart the two displayed means are in absolute terms.

As a general concept, an unadjusted comparison does not incorporate covariates or other adjustments that a model might use. The recalculation is not a substitute for an analysis that accounts for the crossover structure. In particular, the posted summaries do not contain the within-participant covariance needed to reproduce a paired analysis. The reported result should therefore be understood as a simple summary-based recalculation, not as a reconstruction of the sponsor’s model.

What does the sponsor’s ratio estimate express?

The sponsor reports a test-to-reference ratio of least-squares means multiplied by 100 of 95.1, with a 90% confidence interval from 85.8 to 105.4. A ratio comparison places the treatments on a relative scale: values are interpreted in relation to the reference formulation rather than as an absolute difference in ng/mL. Least-squares means are model-based means, which can differ in interpretation from the raw arm means. The registry does not report the model specification, the method used to construct the interval, or a p-value for this analysis.

The ratio-times-100 format makes 100 the point of equal estimated means on that relative scale. This is a general interpretation of the scale, not a stated decision threshold for this study. A formal bioequivalence decision normally depends on prespecified limits and an analysis plan; neither those limits nor the full decision rule is reported in the registry record. Thus, the reported ratio and interval should not be treated as proof that a particular acceptance criterion was met.

Why do the interval and p-value matter?

A confidence interval gives a range of values compatible with the data under the assumptions of the analysis. It conveys uncertainty around an estimate, whereas a point estimate alone gives only one central value. The recalculated interval includes negative and positive differences, which means it allows for either direction of absolute difference as well as a value of zero. The sponsor’s 90% interval is on the ratio-times-100 scale and is not directly comparable with the recalculated interval on the difference scale.

A p-value summarizes how unusual the observed data, or more extreme data, would be under a specified null hypothesis and analysis model. The unadjusted p-value of 0.686 belongs to the recalculated difference comparison. It does not answer the same question as a ratio-based bioequivalence analysis, and the sponsor’s reported ratio analysis has no p-value listed. Statistical interpretation should therefore keep the analysis, scale, and inferential target attached to each result.

What remains unknown about the analysis?

The registry does not identify the sponsor’s statistical model, the treatment of period or sequence effects, the handling of missing observations, the method for calculating the ratio interval, or the prespecified bioequivalence margins. It also does not report whether any interim analyses were planned or conducted, or the trial’s original sample-size justification. These details cannot be inferred from the fact that the study was randomized and crossover. They matter because the model and design assumptions determine how estimates and uncertainty are calculated.

The analysis population is described as subjects who completed the study. The number completing the study, any exclusions from the primary analysis, and any approach to incomplete data are not stated. The arm summaries list 28 participants for each formulation, but those counts do not by themselves explain whether all enrolled participants completed every period or whether any missing observations were handled. These limits apply when interpreting both the descriptive summaries and the sponsor’s analysis.

10. Confidence Intervals and Precision

Precision concerns how narrowly an estimate is located by its uncertainty interval. The unadjusted mean difference is 33.0 ng/mL, with an interval from -126.8 to 192.8. Because this interval extends on both sides of zero, the posted summary-based comparison does not tightly determine whether the absolute mean difference favors one formulation or the other. The registry does not state the confidence level for this recalculated interval, so it should not be assigned a level that is not reported.

The sponsor’s ratio of least-squares means multiplied by 100 is 95.1, and its reported 90% confidence interval extends from 85.8 to 105.4. The interval indicates uncertainty on the relative scale and includes values below and above 100. Its limits are not the same quantity as the limits for the difference interval: one is a relative ratio scale, while the other is an absolute concentration scale.

As a general statistical concept, a confidence interval reflects both the variability in the data and the amount of information used by the analysis. Greater precision would generally be reflected by a narrower interval, but the width cannot be attributed to any one factor from these summaries alone. The crossover structure could be relevant to precision if the analysis used paired information, yet the registry does not report the model details or within-participant covariance. Consequently, the simple recalculation and sponsor interval should be interpreted according to their distinct methods and scales, rather than compared as though they were two estimates of precisely the same quantity.

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 sample-size display is a planning illustration based on the observed effect, not a description of the study’s original design calculation. The figures are participants per arm, not total events. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. For each planning scenario, the effect to detect is the stated fraction of the observed effect. The trial’s own original sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the illustrated number of participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect and the assumptions are correct. The 90% power column gives the corresponding planning figure for a higher target chance of detecting that effect. These are design calculations, not estimates of the probability that the completed study detected a real effect.

The rows use planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. The displayed figures are, respectively, 1,342 and 1,797 participants per arm; 2,386 and 3,194 participants per arm; and 5,368 and 7,186 participants per arm, for the 80% and 90% power columns. The curve presents the same general planning relationship visually: smaller effects require more participants under the stated assumptions.

These values are not observed power. They are illustrations calculated from the observed effect and do not establish what the original investigators planned or why the completed trial enrolled 28 participants. The registry does not report the original design assumptions, and the illustration should not be used as a retrospective judgment of the study’s design.

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 = 33.000; pooled standard deviation σ = 305.104.
2. n = 2 × (1.96 + 0.842)² × 305.104² / 33.000² = 1,341.9, rounded up to 1,342 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 <- 33                      # observed difference in means
sigma <- 305.104187123022                     # 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(833586)
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 = 1,342 (80% power), 1,797 (90% power)
 75% of observed effect: n per arm = 2,386 (80% power), 3,194 (90% power)
 50% of observed effect: n per arm = 5,368 (80% power), 7,186 (90% power)
power.t.test: 1342.8 
Simulated power at n = 1,342 per arm: 0.800 (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 reported analysis is a test-to-reference ratio of least-squares means multiplied by 100: 95.1, with a 90% confidence interval from 85.8 to 105.4. This is the analysis directly reported by the sponsor in the registry. It is on a relative scale and is based on least-squares means. The registry does not provide the model specification, the method used to calculate the interval, or the formal acceptance limits used for a bioequivalence determination.

The recalculated result is a simple unadjusted difference in the posted arm means: 33.0 ng/mL for Lamisil® relative to Terbinafine, with an interval from -126.8 to 192.8 and an unadjusted p-value of 0.686. It is not an alternative calculation of the same ratio estimate. The difference is expressed in ng/mL, while the sponsor’s estimate is relative; the sponsor’s result is also described as based on least-squares means.

The registry does not flag a discrepancy between the posted sponsor analysis and the recalculation. Even so, the distinct scales and analytical approaches mean that the recalculation should not replace the sponsor’s result. The sponsor’s analysis is the relevant posted ratio-based result, while the unadjusted calculation serves as a separate descriptive comparison. Neither result can be interpreted as a formal bioequivalence decision without the margins and decision rules, which are not reported in the registry record.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures and three analyses, and it reports zero secondary outcomes as posted. The primary endpoint described is Cmax. The reported sponsor analysis is a test-to-reference ratio of least-squares means multiplied by 100. The unadjusted recalculation is an additional summary-based comparison, not a substitute for the sponsor’s stated analysis.

Multiplicity arises when several outcomes, comparisons, or analyses are examined. As a general statistical concept, making multiple inferential assessments can increase the chance of at least one apparently notable result, depending on how the analyses are conducted. The registry does not report whether multiplicity adjustments were planned or used, how the three listed outcome measures and three analyses relate to one another, or whether any outcomes were designated secondary in the protocol. No multiplicity correction should therefore be assumed.

The primary analysis population is described as data from all subjects who completed the study. The posted arm summaries each list 28 participants. The registry does not report the number who completed the study, withdrawals, exclusions, or reasons for missing measurements. It also does not report whether missing data occurred, whether imputation was used, or how incomplete crossover records would have been handled. A complete-case description should not be expanded into assumptions about participants who did not complete the study.

The record does not identify an intention-to-treat analysis, a per-protocol analysis, or additional analysis populations. It also does not report an interim-analysis plan or whether interim analyses occurred. The absence of these details does not establish that a particular method was or was not used; it means the registry record does not document the information needed to evaluate those procedures. These gaps limit assessment of how broadly the posted estimate represents enrolled participants and how the reported analysis fits into the full set of planned comparisons.

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

The results describe Cmax values for two terbinafine formulations in a randomized crossover study of healthy adults under fasting conditions. The posted mean was 840.2 ng/mL for the test formulation and 873.2 ng/mL for the Lamisil® reference formulation. The sponsor’s ratio of least-squares means multiplied by 100 was 95.1, with a 90% confidence interval from 85.8 to 105.4. The unadjusted mean-difference recalculation was 33.0 ng/mL, with an interval from -126.8 to 192.8 and an unadjusted p-value of 0.686.

These results describe measured peak concentration and uncertainty around estimates. They do not, by themselves, establish the formal outcome of a bioequivalence assessment. Although the endpoint description states that bioequivalence was based on Cmax, the registry does not report the acceptance margins, the complete statistical model, or the decision rules. Without those elements, a reader cannot determine from the registry record alone whether the sponsor applied a particular prespecified criterion or how it was applied.

The findings also do not establish equivalence for all pharmacokinetic characteristics, other conditions of use, or outcomes beyond the posted endpoint. The study was conducted in healthy participants under fasting conditions, and its population description does not include patients with a specified condition. The registry record does not provide clinical outcomes, safety findings, or evidence about use in other populations. Cmax is one measure of plasma concentration, not a complete account of every possible treatment effect.

As a general interpretation, estimates are most useful when read together with their uncertainty and the analysis that produced them. The sponsor’s ratio result and the recalculated absolute difference use different scales and analytical approaches. Neither should be turned into a medical recommendation. The results support a statistical description of the posted pharmacokinetic comparison, while leaving important details of the formal bioequivalence determination and broader clinical implications unreported.

16. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates how a randomized crossover design and a ratio-based pharmacokinetic question produce results that should be distinguished from a simple difference between arm means. Each sequence included both formulations, making the participant-level pairing potentially relevant to the analysis. The registry reports the sponsor’s ratio of least-squares means, but not the model used to obtain it. The posted arm summaries permit a separate, unadjusted comparison, yet they do not contain all the information needed to recreate a paired crossover analysis.

The comparison also illustrates why the scale of an estimate matters. A difference in ng/mL describes absolute separation between mean concentrations, whereas a test-to-reference ratio describes relative concentration. A confidence interval on one scale cannot be substituted for an interval on the other. The sponsor’s ratio estimate of 95.1 and its 90% interval from 85.8 to 105.4 directly describe the reported relative analysis; the recalculated difference and its interval describe a distinct summary-based analysis.

Finally, the record highlights the importance of reporting decision rules alongside results. A bioequivalence label depends on more than a point estimate: interpretation requires the relevant prespecified limits and analytic details. Those details are not reported in the registry record. The posted data therefore offer a useful example of separating estimates, uncertainty, model-based analysis, and formal decision criteria, without claiming more than the available record documents.

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.

Several trial-specific details needed for a complete assessment are not reported in the registry record. The sponsor’s statistical method is not specified, despite the reported least-squares-mean ratio. The record does not identify the model terms, explain how treatment, period, or sequence were addressed, or provide the method for constructing the reported 90% confidence interval. The formal bioequivalence margins and decision rule are also not reported.

The registry describes a crossover with test-first and reference-first sequences, but does not report the length of each period, a washout interval, or other period conduct details. These omissions make it difficult to assess design features that could matter in interpreting repeated measurements. The record also does not describe the randomization procedure beyond identifying the study as randomized or state why masking was not used beyond listing masking as none.

The primary analysis population is described as subjects who completed the study, but the number completing, any withdrawals, exclusions, and missing observations are not reported. The arm summaries list 28 participants for each formulation, but they do not provide individual paired measurements or the within-participant covariance. Consequently, the simple recalculation cannot reproduce any paired model-based analysis that may have been used.

The posted endpoint is Cmax, and the study population was healthy adults under fasting conditions. The registry record does not report results for other populations or conditions, nor does it provide clinical outcome findings. Its listed outcomes and analyses are not accompanied by enough detail to assess multiplicity procedures. These limitations define what can be concluded from the registry record; they do not establish that unreported procedures were absent from the study.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Terbinafine HCl 250 mg Tablet Under Fasting Conditions — NCT00833586.
• Registry record last updated 2024-08-19; status last verified 2024-08.
• 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

NCT00833586 is a completed Phase 1 randomized, unmasked crossover study sponsored by Teva Pharmaceuticals USA. It enrolled 28 healthy adult male and female participants who did not use tobacco and assessed Terbinafine HCl 250 mg tablets against Lamisil® 250 mg tablets under fasting conditions. Each sequence included both formulations in opposite period orders.

The primary endpoint was plasma Cmax, with blood samples collected over a 144 hour period. The posted sponsor result was a test-to-reference ratio of least-squares means multiplied by 100 of 95.1, with a 90% confidence interval from 85.8 to 105.4. A separate unadjusted recalculation reported a mean difference of 33.0 ng/mL, an interval from -126.8 to 192.8, and an unadjusted p-value of 0.686.

The registry does not report the sponsor’s model details or the formal bioequivalence margins and decision rule. The posted estimates should therefore be interpreted according to their distinct scales and with those limitations in mind.