Bioequivalence of Losartan and Hydrochlorothiazide (HCTZ) Combination Tablet and Coadministration of Its Components (0954A-306): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bioequivalence of Losartan and Hydrochlorothiazide (HCTZ) Combination Tablet and Coadministration of Its Components (0954A-306) (NCT00953680), a randomized phase 1 study. The primary outcome is Area Under the Curve (AUC(0 to Infinity)) of Losartan.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, 2-period crossover study in healthy adults. Each study treatment was a single dose: losartan 100 mg with hydrochlorothiazide 12.5 mg in one combination tablet, or a losartan 100 mg tablet coadministered with a hydrochlorothiazide 12.5 mg capsule. In a crossover design, participants receive the treatments in a sequence, so the comparison can use measurements from the same people under each treatment. The registry does not report the treatment sequences, the interval between periods, or other details of period conduct.

The trial was listed as Phase 1 and enrolled 77 participants. It started in 2004-04, had primary completion in 2004-05, and is recorded as completed. Masking was none. The sponsor was Organon and Co. The registry record describes the study as evaluating bioequivalence, but the original protocol’s design assumptions and full statistical plan are not reported in the registry record.

The primary endpoint was the area under the curve for losartan, with a stated timeframe of 0 to 36 Hours Post Dose. Its title specifies AUC(0 to Infinity), and its unit is ng*hr/mL. The analysis record reports data from 75 participants for each treatment. The narrative says complete pharmacokinetic data were available from 75 of 77 subjects, with 1 replacement; it also notes that partial data from 1 subject were not analyzed and that another subject had undetectable plasma concentrations following 1 treatment, with partial data excluded from analyses. These details mean the enrollment count and the outcome-analysis counts are not interchangeable.

The registry lists four outcome measures and four analyses, but no secondary outcomes are posted. It does not report the randomization procedure, washout interval, sample-size justification, or a fuller account of how the analysis handled participant, period, or sequence effects.

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.

Period 1

Reasons for not completing this period:

Period 2

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) results included complete data from 75 of 77 subjects (with 1 replacement). Partial data from 1 subject were not analyzed. Plasma concentrations for another subject were undetectable following 1 treatment, with partial data excluded from analyses.

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 Area Under the Curve (AUC(0 to Infinity)) of Losartan, measured over 0 to 36 Hours Post Dose.

The primary endpoint measures losartan exposure over time after dosing. Area under the concentration-time curve, or AUC, summarizes the concentration of a drug in plasma across a stated interval. It is used in pharmacokinetic comparisons because it reflects overall exposure rather than a concentration at one sampling time. The registry names the endpoint Area Under the Curve (AUC(0 to Infinity)) of Losartan, gives ng*hr/mL as its unit, and lists the timeframe as 0 to 36 Hours Post Dose. Both labels are retained because the record reports them in those terms.

The posted treatment values are least-squares means, accompanied by standard deviations. The sponsor’s analysis reports a least-squares mean ratio, which expresses the comparison on a relative scale. For a bioequivalence question, a ratio-based estimate and its confidence interval help describe how closely the measured exposures align. The registry does not report the prespecified acceptance limits used for the sponsor’s assessment, so the endpoint estimate alone does not establish the decision rule.

This pharmacokinetic measure is not itself a blood-pressure outcome. Although Hypertension is listed as a condition, participants are described as healthy adults, and the primary endpoint is drug exposure. The registry record does not report evidence about longer-term clinical outcomes.

7. Results Posted in the Registry

• Losartan Tablet + HCTZ Capsule: mean 1,025 versus 1,018 on control; difference 6.80 (95% CI -111.24 to 124.84), standardized effect d = 0.02; z-test p = 0.910.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a crossover design compare?

In a crossover trial, participants receive more than one treatment in different periods. Each participant can therefore contribute measurements under both treatments, making the person their own reference for some aspects of the comparison. This can reduce the influence of stable differences between people. It also makes period effects, sequence effects, and the correlation between a participant’s measurements important to analysis. The registry identifies a randomized, 2-period crossover design but does not report the treatment sequences, the interval between periods, or the specific model used to account for these features.

What does a least-squares mean represent?

A least-squares mean is an estimated group mean from a statistical model. Depending on the model, it can account for design factors and other terms rather than simply averaging all observed values. The registry identifies the primary arm summaries as least-squares means, but the sponsor’s model details are not reported in the registry record. The posted means are 1018.0 and 1025.0 ng*hr/mL, with standard deviations of 382.5 and 354.6.

Why use a ratio for bioequivalence?

A ratio describes one treatment’s estimated exposure relative to the other treatment’s estimated exposure. Ratios are useful for bioequivalence questions because the question concerns relative exposure, not only an absolute difference in concentration-time area. The sponsor-reported least-squares mean ratio is 0.993, with a 90% confidence interval from 0.950 to 1.039. In general, a formal equivalence conclusion compares the confidence interval with prespecified acceptance limits. Those limits and the full analysis specification are not reported in the registry record, so the ratio and interval can be interpreted descriptively but cannot supply the missing decision rule.

What is the unadjusted re-calculation?

The separate re-calculation compares posted summary statistics on an absolute mean-difference scale. It gives a mean difference of 6.8, a 95% confidence interval from -111.2 to 124.8, and an unadjusted p-value of 0.91. The pooled standard deviation used in the calculation is 368.8 and is marked as approximate. In general, a pooled standard deviation combines information about spread across groups to describe variability for a two-group comparison.

This re-calculation is not a replacement for the sponsor’s crossover analysis. It is a simple, unadjusted comparison based on summary values. The posted arm summaries do not include the within-participant covariance needed to reproduce a paired analysis, and the re-calculation therefore does not use the full crossover structure. Its interval and p-value answer a different, more limited question than the sponsor’s reported ratio analysis.

Why can over-dispersion matter?

In general, over-dispersion means that observed variability is greater than a statistical model expects. When variability is larger than assumed, standard errors may be understated and confidence intervals may be too narrow if the model does not allow for the extra spread. For this endpoint, the posted standard deviations are substantial relative to the arm means, but the registry does not report a model diagnostic or an over-dispersion analysis. No conclusion about a particular variance model can be drawn from the record.

What do the p-value and confidence interval contribute?

In general, a p-value describes how incompatible the observed data are with a specified null hypothesis under the model used. It does not measure the probability that a hypothesis is true, and it does not establish equivalence. A confidence interval gives a range of values compatible with the estimate and its uncertainty under the analysis assumptions. The re-calculated p-value is unadjusted, and its interval is for the mean difference. The sponsor’s 90% interval pertains to a ratio and to the sponsor-reported analysis. Because the estimands and scales differ, the two intervals should not be treated as interchangeable.

What is not documented?

The registry record does not report the sponsor’s complete statistical model, the equivalence margins, the original sample-size justification, or interim analyses. It also does not provide the paired covariance, detailed period and sequence handling, or a complete account of how missing pharmacokinetic observations were handled. These omissions limit independent reconstruction and formal assessment of the analysis, even though the posted primary estimate and interval are available.

10. Confidence Intervals and Precision

Precision concerns how tightly an estimate is determined by the data and analysis. A confidence interval communicates this uncertainty by giving a range of values compatible with the estimate under the specified analysis assumptions. It is not a guarantee that the true value lies in the interval, nor does it account for design or analysis features that were not modeled or reported.

The sponsor-reported least-squares mean ratio is 0.993, with a 90% confidence interval from 0.950 to 1.039. This interval describes uncertainty on a relative scale. For an equivalence interpretation, its position must be assessed against prespecified limits. Those limits are not reported in the registry record, so the interval cannot be used to verify whether a formal criterion was met.

The unadjusted re-calculation reports a mean difference of 6.8 and a 95% confidence interval from -111.2 to 124.8. This interval is on an absolute scale and is based on an approximate pooled standard deviation of 368.8. It does not incorporate the pairing information that would be needed to reproduce a crossover analysis. It therefore offers a limited view of precision and should not be substituted for the sponsor’s ratio interval.

The posted standard deviations, 382.5 and 354.6, describe variability among the analyzed observations. They are not confidence intervals and do not show uncertainty in the estimated treatment contrast by themselves. The registry does not report the within-person correlation, full model, or equivalence bounds; each omission matters when evaluating precision and the meaning of the sponsor’s result.

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 and 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. These are planning assumptions for the illustration; the trial’s original design assumptions are not reported in the registry record.

The 80% power column gives the planned number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if that effect and the model assumptions were correct. The 90% power column describes the corresponding planning target for a 90% chance. These values are not observed power. The illustration is not a retrospective measure of how likely the completed trial was to find a treatment difference.

The effect scenarios are 100%, 75%, and 50% of the observed effect. For 100% of the observed effect, the figures are 46,178 participants per arm for 80% power and 61,820 for 90% power. For 75% of the observed effect, they are 82,095 and 109,901 participants per arm. For 50% of the observed effect, they are 184,712 and 247,277 participants per arm. Smaller effects require more participants under the stated assumptions, because they are harder to distinguish from random variation.

These calculations use an equal-allocation, two-arm normal approximation. They are not the original crossover trial’s sample-size justification and should not be read as a recommended design for a crossover study. The registry does not report the assumptions used to plan the completed trial.

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 = 6.800; pooled standard deviation σ = 368.814.
2. n = 2 × (1.96 + 0.842)² × 368.814² / 6.800² = 46,177.9, rounded up to 46,178 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 <- 6.80000000000007                      # observed difference in means
sigma <- 368.813916494484                     # 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(953680)
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 = 46,178 (80% power), 61,820 (90% power)
 75% of observed effect: n per arm = 82,095 (80% power), 109,901 (90% power)
 50% of observed effect: n per arm = 184,712 (80% power), 247,277 (90% power)
power.t.test: 46178.9 
Simulated power at n = 46,178 per arm: 0.804 (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-reported result is a least-squares mean ratio of 0.993, with a 90% confidence interval from 0.950 to 1.039. It is identified as a legacy non-inferiority-or-equivalence analysis. The registry does not report the method details or the acceptance limits used for the sponsor’s assessment, so those criteria cannot be checked from the record.

The separate re-calculation is an unadjusted mean-difference comparison using posted summary statistics. It gives a mean difference of 6.8, a 95% confidence interval from -111.2 to 124.8, and an unadjusted p-value of 0.91. It uses an approximate pooled standard deviation and does not reproduce the sponsor’s crossover model or ratio estimand. The two analyses consequently differ in scale, estimand, and treatment of the study design.

The discrepancy indicator is false, but that does not make the re-calculation equivalent to the sponsor’s analysis. The sponsor’s estimate is the registry’s reported analysis; the re-calculation is a supplementary, unadjusted check based on the posted summaries. It should not be used to replace or reinterpret the sponsor’s analysis as though it incorporated the same model.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and four analyses, but no secondary outcomes are posted. It does not describe a multiplicity adjustment, a hierarchy among outcomes, or a plan for controlling error across multiple comparisons. Without the analysis plan, it is not possible to determine whether adjustments were planned or whether the posted analyses represent all prespecified outcomes.

The primary endpoint’s result is available as a sponsor-reported least-squares mean ratio and confidence interval. The registry does not report the complete statistical model, the equivalence limits, or the full testing procedure. The re-calculated p-value of 0.91 is explicitly unadjusted and does not address multiplicity or establish equivalence. No claim about an unreported adjustment should be inferred.

Missing pharmacokinetic data are described in the endpoint record. Complete data were available from 75 of 77 subjects, with 1 replacement. Partial data from 1 subject were not analyzed. Plasma concentrations for another subject were undetectable following 1 treatment, with partial data excluded from analyses. The posted analysis reports 75 observations for each treatment. The record does not give a fuller participant-level flow, explain the replacement’s handling in the analysis set, or describe any imputation or sensitivity analysis.

The analysis population is identified as pharmacokinetic results, but the registry does not report a detailed definition of the population or whether it was specified in a protocol. It also does not provide enough information to assess how exclusions affected the paired comparison. In a crossover design, incomplete data for one treatment can affect whether a participant contributes a complete within-person comparison. The record’s description establishes that data were excluded, but not the full consequences for the model or estimand.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports no serious adverse events among the participants at risk in either treatment sequence: 0 of 38 for the sequence listed as Losartan-HCTZ Combination Tablet/Losartan Tablet +HCTZ Capsule, and 0 of 39 for the reverse sequence. These are sequence-group counts, not counts separated by treatment period. The record does not report deaths for these groups.

Other adverse events are listed for 12 of 76 at risk in the first sequence group and 10 of 77 in the reverse sequence group. These are distinct from the serious adverse event counts and should not be combined with them. No serious adverse event terms are listed. The adverse-event record alone does not establish comparative safety, particularly because the study was a single-dose pharmacokinetic comparison in healthy adults and the registry does not provide event descriptions or a detailed safety analysis.

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

The posted results describe losartan exposure after a single dose of the combination tablet and after coadministration of separate losartan and hydrochlorothiazide products. The sponsor’s least-squares mean ratio is 0.993, with a 90% confidence interval from 0.950 to 1.039. This gives the estimated relative comparison and its uncertainty for the primary pharmacokinetic measure.

The result is relevant to a bioequivalence question, but the registry record does not report the acceptance limits or full statistical method needed to independently verify a formal equivalence decision. The unadjusted re-calculation is a different comparison: it gives a mean difference of 6.8, with a 95% confidence interval from -111.2 to 124.8 and an unadjusted p-value of 0.91. It does not reproduce the sponsor’s crossover analysis, and a non-significant difference test is not the same as demonstrating equivalence.

The trial does not answer whether either presentation changes blood pressure or improves any clinical outcome. Its primary measure is losartan exposure over the recorded post-dose timeframe, not a clinical endpoint. The population is described as healthy adults, and the registry does not post secondary outcomes. Findings from this short pharmacokinetic comparison therefore should not be extended to longer-term outcomes or to populations not described in the record.

The posted adverse-event counts include no serious adverse events in either treatment sequence group, but these counts do not establish that serious events cannot occur or that the treatments have identical safety profiles. The record’s adverse-event information is limited, and the study’s scope is pharmacokinetic comparison rather than a broad evaluation of clinical safety.

17. Why This Trial Matters Statistically

This trial illustrates why the analysis scale must match the scientific question. A mean difference describes an absolute contrast, while a mean ratio describes a relative contrast. Bioequivalence questions commonly focus on relative exposure, so the sponsor’s ratio and its confidence interval are central to understanding the posted analysis. A separate unadjusted difference calculation can provide context, but it is not a substitute for the sponsor’s model.

The crossover design also matters statistically. Measurements from the same participant are related, and paired analysis can use that structure. Reconstructing such an analysis requires information about the relationship between each participant’s treatment measurements and the model’s handling of period and sequence. Those details are not reported in the registry record. The re-calculation based on group summaries therefore has a narrower interpretation than a fully specified crossover analysis.

Equivalence is not established merely by failing to find a statistically significant difference. It depends on a prespecified range of acceptable relative differences and an appropriate confidence interval. The record reports a 90% interval for the least-squares mean ratio but does not give the acceptance limits. This makes the distinction between a numerical result and a decision rule especially important.

Finally, the sample-size illustrations show how planning depends on the effect size targeted: smaller effects require more participants under the stated assumptions. They are not evidence of observed power and are not the study’s original design justification. Together, these features show why interpretation requires attention to estimand, design, uncertainty, and the completeness of registry reporting.

18. Limitations

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

The registry record does not report the equivalence acceptance limits, the complete sponsor model, or the original sample-size justification. Without these, the sponsor’s ratio and interval can be described but not independently evaluated against the intended decision criteria. The treatment sequences and interval between crossover periods are also not reported.

The unadjusted re-calculation uses summary statistics and an approximate pooled standard deviation. It does not use the participant-level pairing that is central to a crossover analysis; the within-participant covariance is not reported. It should therefore be regarded as a limited supplementary calculation rather than a reconstruction of the primary analysis.

The available-data description includes exclusions for partial or undetectable concentration data and a replacement, but the registry does not give a full participant flow or sensitivity analyses. The impact of these exclusions on the sponsor’s analysis cannot be assessed from the posted record. The record lists four outcome measures and analyses but posts no secondary outcomes, and it does not report a multiplicity plan.

The study involved single-dose pharmacokinetic measurements in healthy adults. Its primary endpoint is losartan exposure, not a clinical outcome, and the record does not establish conclusions about longer-term effects. Safety reporting is also limited: serious adverse event counts are listed by sequence group, but detailed event descriptions and a comprehensive safety analysis are not reported in the registry record.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Bioequivalence of Losartan and Hydrochlorothiazide (HCTZ) Combination Tablet and Coadministration of Its Components (0954A-306) — NCT00953680.
• Registry record last updated 2022-02-09; status last verified 2022-02.
• Results first posted 2010-07-16.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

This completed Phase 1 study was randomized, open-label, and used a 2-period crossover design. It enrolled 77 healthy adults and compared a single dose of losartan 100 mg/hydrochlorothiazide 12.5 mg in a combination tablet with coadministration of a losartan 100 mg tablet and a hydrochlorothiazide 12.5 mg capsule.

The primary endpoint was losartan AUC, titled AUC(0 to Infinity), with a timeframe of 0 to 36 Hours Post Dose and units of ng*hr/mL. The sponsor-reported least-squares mean ratio was 0.993, with a 90% confidence interval from 0.950 to 1.039. The registry does not report the equivalence limits or full model details needed to independently assess the formal decision criteria.

The record describes exclusions for partial or undetectable data and reports 75 observations per treatment. It lists no serious adverse events in either sequence group. No secondary outcomes are posted.