Losartan Potassium/Hydrochlorothiazide 100/25 mg Tablets in Healthy Subjects Under Non-Fasting Conditions: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Losartan Potassium/Hydrochlorothiazide 100/25 mg Tablets in Healthy Subjects Under Non-Fasting Conditions (NCT01149473), a randomized phase 1 study. The primary outcome is Cmax of Losartan(Maximum Observed Concentration of Drug Substance in Plasma).

2. Clinical Question

The study asked whether the relative bioavailability of the Teva losartan potassium/hydrochlorothiazide 100/25 mg tablet differed from that of Hyzaar® 100/25 mg tablets under non-fasting conditions. Relative bioavailability describes how drug exposure from one product compares with exposure from another. The primary endpoint was the maximum observed concentration of losartan in plasma, called Cmax.

This is a pharmacokinetic comparison in healthy subjects, not a study of symptom improvement or clinical outcomes. The registry record does not report a clinical efficacy question. The result therefore describes a measured concentration endpoint and its uncertainty; it does not, by itself, establish how either product affects health outcomes.

3. Trial Design

The registry classifies this as a phase 1, randomized, open-label crossover study. It lists 80 participants as enrolled and gives the study status as completed. The recorded start was 2004-03, and primary completion was 2004-04. The sponsor was Teva Pharmaceuticals USA.

A crossover design compares treatments by having participants receive more than one treatment over the course of a study. In general, this allows comparison within the same participant, which can account for some differences between people. The registry identifies this study as a crossover, but the treatment sequence, timing between treatments, and other details of the crossover conduct are not reported in the registry record. The randomization procedure is also not described beyond the randomized classification.

The study was not masked. That means the registry classifies it as open-label; it does not report that participants or study staff were blinded to treatment assignment. The listed arms are the losartan/hydrochlorothiazide test product and Hyzaar® reference product, both at 100/25 mg.

The primary endpoint results list 76 participants for each treatment group. The safety record lists 80 participants at risk in each group. These figures describe different posted results and should not be treated as a single participant count. The registry does not explain the difference between the enrollment figure and the analyzed primary-endpoint counts, nor does it report details of participant flow or reasons for any missing endpoint observations.

The registry identifies the subjects as healthy and the brief description as covering healthy, adult, non-smoking subjects under non-fasting conditions. It does not report the original sample-size rationale, treatment sequence details, or the study’s full statistical analysis plan.

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

Reasons for not completing this period:

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 of Losartan(Maximum Observed Concentration of Drug Substance in Plasma), measured over Blood samples collected over a 48 hour period..

The primary endpoint is losartan Cmax: the maximum observed concentration of losartan in plasma after treatment. Concentration was measured in ng/mL, and blood samples were collected over a 48 hour period. The registry describes the endpoint as a mean of a continuous measure, with standard deviation as the measure of spread.

Cmax is used in pharmacokinetic comparisons because it summarizes the highest observed plasma concentration during the sampling period. Comparing this measure between products can help characterize whether they produce similar peak exposure under the study conditions. It is one aspect of drug exposure, rather than a direct measurement of clinical benefit or harm.

The registry states that bioequivalence was assessed based on losartan Cmax. It also reports a sponsor analysis as the ratio of the test-to-reference geometric means multiplied by 100. The reported value is 109, with a 90% confidence interval from 98.1 to 120. The registry record does not report the acceptance bounds used to interpret that interval, so the posted endpoint figures alone do not establish whether a prespecified bioequivalence criterion was met.

The primary endpoint population is described as all participants who completed the study and had their samples analyzed. The record does not give further detail about sample collection completeness, handling of values below a measurement limit, or exclusions from the analysis.

7. Results Posted in the Registry

• Losartan/HCTZ (Test): mean 458.29 versus 409.32 on control; difference 48.97 (95% CI -43.18 to 141.11), standardized effect d = 0.17; z-test p = 0.298.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is continuous: Cmax is recorded as a concentration, rather than as a category such as event or no event. The registry reports a mean for each treatment group and uses standard deviation to describe variation among observations. The mean locates the center of the observed values, while the standard deviation describes how dispersed the measurements are around that center. A large spread means that individual observations vary substantially; it does not, by itself, determine whether a treatment comparison is precise.

What does a mean difference represent?

The recalculated comparison expresses the test-product mean minus the reference-product mean on the concentration scale. Its estimate is 48.97 ng/mL. A difference of zero would correspond to equal group means on this scale. The 95% confidence interval, from -43.18 to 141.1, describes the uncertainty around the estimate under the calculation’s assumptions. Because this interval includes zero, the summary-statistic comparison does not distinguish the observed difference clearly from no mean difference.

This is an unadjusted recalculation from the posted summary statistics. It is not reported as the sponsor’s analysis. In a crossover study, observations from the same participant may be related across treatments. A paired analysis can use that within-participant relationship. The group means and standard deviations alone do not provide the paired differences or their variability, so the recalculation cannot recover that component of a crossover analysis.

Why report a geometric-mean ratio?

The sponsor’s posted result uses a ratio of test-to-reference geometric means multiplied by 100. A ratio compares the two products on a relative scale, whereas a mean difference describes an absolute change in the original measurement units. A geometric mean is commonly used for positively valued measurements that are analyzed on a logarithmic scale; on returning to the original scale, comparisons can be expressed as ratios. This is a general statistical explanation, not a statement about the unreported details of the sponsor’s method.

The recorded ratio is 109, with a 90% confidence interval from 98.1 to 120. The registry labels this analysis as a legacy non-inferiority-or-equivalence type but does not provide the analysis method, decision bounds, or a p-value. The label and interval alone are insufficient to infer the sponsor’s exact decision rule or conclusion. The reported ratio should therefore be read as the sponsor’s posted relative-scale estimate, with its stated uncertainty.

How should the confidence intervals be understood?

A confidence interval is a range of values compatible with the observed data under the statistical model used to calculate it. It conveys uncertainty in an estimate; it is not a range containing a specified proportion of individual participants’ measurements. The 95% interval accompanies the recalculated mean difference. The sponsor’s ratio is accompanied by a 90% interval. Their differing scales and confidence levels mean they should not be compared as though they were the same analysis.

For a mean difference, an interval spanning zero is consistent with a range of possibilities that includes no difference. For a ratio, the corresponding no-difference value is a ratio of one, or 100 when expressed as a percentage. The reported sponsor interval extends from 98.1 to 120. Whether that interval satisfies any formal equivalence criterion depends on decision bounds, which are not reported in the registry record. This general interpretation does not supply those missing bounds.

What does the p-value add?

The recalculated unadjusted p-value is 0.298. In general, a p-value describes how compatible the observed data are with a specified null hypothesis under the assumptions of a statistical test. It is not the probability that the null hypothesis is true, nor does it quantify the probability that a result is clinically important. The registry record does not report a p-value for the sponsor’s ratio analysis or the sponsor’s significance threshold for that analysis.

The planning illustration separately specifies a two-sided significance level of 0.05 for its sample-size calculations. That planning assumption is not evidence that the original trial used the same threshold for its analysis. The original design assumptions and full statistical analysis plan are not reported in the registry record.

What is not recoverable from these summaries?

The posted arm-level means, standard deviations, and participant counts support descriptive summaries and an unadjusted comparison. They do not reveal participant-level distributions, the correlation between each participant’s measurements under the two treatments, or whether outliers influenced the estimates. They also do not identify the sponsor’s model, transformations, sequence or period adjustments, or missing-data procedures. Those details matter when interpreting a crossover analysis, but they should not be guessed from the design label.

Six outcome measures and six analyses are listed, while the record identifies this Cmax measure as primary and posts no secondary outcome results. Whether the original analysis adjusted for multiple comparisons is not reported. In general, multiplicity can increase the chance of a false-positive result when several hypotheses are tested, and prespecified methods can address that issue. The available record does not establish which, if any, such methods were used.

10. Confidence Intervals and Precision

The recalculated mean difference is 48.97 ng/mL, and its 95% confidence interval runs from -43.18 to 141.1. This interval is wide enough to include values on both sides of zero. In plain terms, the posted summary statistics do not pin down the direction or size of the mean difference with high precision. The point estimate is only one possible value within the range of uncertainty.

The sponsor’s result is on a relative scale: a test-to-reference geometric-mean ratio multiplied by 100 of 109, with a 90% confidence interval from 98.1 to 120. This interval also expresses uncertainty, but it cannot be read as if it were the mean-difference interval. A ratio’s reference value for no relative difference is 100, while a difference’s reference value is zero.

Confidence intervals are estimates of uncertainty under a statistical model; they do not describe the spread of individual Cmax measurements. The group standard deviations, 323.3 for the test product and 251.9 for the reference product, describe that observed spread. The crossover structure may also be relevant to precision because within-participant comparisons can differ from comparisons that treat group summaries independently. The posted summaries do not include the paired data needed to quantify that relationship.

The registry does not report the sponsor’s analysis method or the decision bounds for its bioequivalence assessment. Although the sponsor’s interval is reported, its formal interpretation cannot be established from the interval alone. The recalculated interval is a supplementary, unadjusted estimate and does not replace 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 an illustration based on the observed effect, not a report of the trial’s original design calculation. The 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 to a stated fraction of the observed effect. The original trial’s sample-size assumptions are not reported in the registry record.

For planning at 100% of the observed effect, the illustration gives 550 participants per arm for 80% power and 737 participants per arm for 90% power. At 75% of the observed effect, it gives 978 participants per arm for 80% power and 1,309 participants per arm for 90% power. At 50% of the observed effect, it gives 2,200 participants per arm for 80% power and 2,945 participants per arm for 90% power.

In general, power is the chance that a study will detect an effect of the specified size under the planning assumptions, if that effect is present. The 80% and 90% columns show different target probabilities of detecting the assumed effect. A higher target power calls for more participants under the same assumptions. The figures also illustrate that smaller effects need more participants to detect than larger effects.

These are planning illustrations, not observed power. They do not describe the actual power of this completed study, and they should not be used to infer why the original study enrolled its participants. The illustration is based on the observed effect and its stated assumptions, rather than the trial’s original design rationale.

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 = 48.966; pooled standard deviation σ = 289.822.
2. n = 2 × (1.96 + 0.842)² × 289.822² / 48.966² = 549.9, rounded up to 550 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 <- 48.966                      # observed difference in means
sigma <- 289.821935333577                     # 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(1149473)
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 = 550 (80% power), 737 (90% power)
 75% of observed effect: n per arm = 978 (80% power), 1,309 (90% power)
 50% of observed effect: n per arm = 2,200 (80% power), 2,945 (90% power)
power.t.test: 550.9 
Simulated power at n = 550 per arm: 0.796 (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 reports the sponsor’s analysis as a test-to-reference geometric-mean ratio multiplied by 100. The estimate is 109, with a 90% confidence interval from 98.1 to 120. The analysis method and any formal decision bounds are not reported in the registry record. The registry also does not give a sponsor-analysis p-value.

The recalculation is a separate, unadjusted comparison of the posted arithmetic means. It estimates a mean difference of 48.97 ng/mL, with a 95% confidence interval from -43.18 to 141.1 and an unadjusted p-value of 0.298. Because one analysis uses a relative ratio and the other an absolute difference, and because their reported confidence levels differ, their estimates are not interchangeable.

The study is identified as a crossover, while the recalculation uses group-level summary statistics and does not reconstruct a within-participant analysis. The sponsor’s method is not reported, so the precise relationship between its analysis and the crossover structure cannot be assessed. No discrepancy is flagged in the registry record. The sponsor’s posted result should be read as its own reported analysis, while the recalculation offers a distinct descriptive comparison rather than a substitute or a direct replication.

The registry labels the sponsor analysis as a legacy non-inferiority-or-equivalence type. That classification does not disclose the criterion used to reach a conclusion. Without the decision bounds and analysis details, the reported ratio and interval should not be converted into an unsupported claim that a formal equivalence requirement was met or not met.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and six analyses. It identifies losartan Cmax as the primary endpoint and reports no secondary outcome results in the record described. The presence of several listed measures raises a general statistical question about multiplicity: when multiple hypotheses are tested, the chance of at least one false-positive finding can increase. Statistical plans may address this through prespecified outcome hierarchies or adjustments, but whether such methods were used is not reported in the registry record.

The record does not provide a full analysis plan, the sponsor’s analysis method, or a description of which analyses were prespecified. It also does not report the original significance threshold for the primary comparison. The planning illustration’s two-sided significance level of 0.05 applies to that illustration and does not establish the threshold used in the trial’s analysis.

The primary endpoint population is described as all participants who completed the study and had samples analyzed. The endpoint results list 76 participants in each group. The record reports enrollment of 80, but does not explain the difference between that figure and the endpoint counts or identify reasons for missing endpoint observations. It does not report imputation, exclusions, or sensitivity analyses for missing data. It would therefore be inappropriate to assume that missing observations were absent, imputed, or handled in a particular way.

The safety record lists 80 participants at risk in each treatment group, whereas the Cmax results list 76 participants in each group. These are separate posted population counts, and the registry does not explain their relationship. Because the study is a crossover, the same participant may contribute observations under more than one treatment; the arm counts should not be interpreted as evidence that the two groups consist of separate sets of people.

For a crossover study, sequence, period, and within-participant features can be important to analysis. The registry identifies the crossover design but does not report the treatment sequences, period details, paired data, or whether these features were included in the sponsor’s model. The available record therefore supports only limited assessment of analysis populations, missing-data handling, and multiplicity.

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 5% reporting threshold.

The registry lists 80 participants at risk for serious adverse events in the test-product group and 80 in the reference-product group. The serious adverse event count is 0 in each group. It also lists 80 participants at risk for other adverse events in each group, with 0 affected in each group. These are the posted counts; they do not establish that every possible adverse event was assessed or recorded in the same way.

The death fields are not populated with a count. Deaths are therefore not reported in the registry record, rather than being established as zero. No serious adverse event terms are listed. The record does not provide additional detail on event definitions, collection procedures, timing, severity, or the relationship of any event to treatment.

These safety figures describe the registry’s recorded counts in this study. They are not a substitute for a detailed safety assessment, and the study was conducted in healthy subjects for a relative-bioavailability question. The counts should be interpreted in that context without extrapolating to other populations or making clinical recommendations.

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

The results describe peak plasma concentrations of losartan after the test and reference products were studied under non-fasting conditions in healthy subjects. The group means were 458.3 ng/mL for the test product and 409.3 ng/mL for the reference product, with 76 participants listed in each group. The unadjusted mean-difference estimate is 48.97 ng/mL, with a 95% confidence interval from -43.18 to 141.1. This interval shows substantial uncertainty around the difference and includes zero.

The sponsor separately reports a geometric-mean ratio of 109, expressed as a test-to-reference ratio multiplied by 100, with a 90% confidence interval from 98.1 to 120. The two estimates use different scales and methods cannot be assumed to be identical. The sponsor’s method and the decision bounds for its bioequivalence assessment are not reported in the registry record. Consequently, the reported ratio does not, on its own, establish a formal bioequivalence conclusion.

The trial concerns a pharmacokinetic measure, not clinical outcomes. Cmax describes the highest observed concentration in plasma during the stated sampling period. The results do not show whether either product changes symptoms, prevents disease, or affects outcomes beyond this concentration measure. They also do not establish how results would apply to people who are not healthy subjects or to conditions other than the non-fasting study setting.

The crossover classification indicates that participants received more than one treatment, but detailed sequence and period information is not reported. The recalculation is unadjusted and based on group summary statistics, not participant-level paired observations. It therefore should be kept distinct from the sponsor’s posted analysis. The record supports a description of the endpoint estimates, uncertainty, and posted safety counts; it does not support stronger claims about clinical effects or a formal equivalence decision.

17. Why This Trial Matters Statistically

This study is statistically useful because it illustrates how a relative-bioavailability question can have more than one legitimate summary scale. The sponsor reports a geometric-mean ratio, while the recalculation reports an arithmetic mean difference. A ratio describes relative exposure, and a difference describes an absolute change in the measurement units. Keeping those scales distinct prevents an estimate from being interpreted as though it answered a different question.

The crossover design also matters. General statistical reasoning recognizes that measurements from the same person under different treatments may be related. A within-participant analysis can use that relationship, whereas an unadjusted comparison of group summaries cannot recover it without the paired observations. The registry does not report the details needed to assess the sponsor’s use of the crossover structure, so the recalculation is best understood as a separate, limited summary.

Precision is another important feature. The recalculated interval spans negative and positive mean differences, and the sponsor’s relative-scale interval is reported without its decision bounds. These intervals show why point estimates alone are insufficient for interpretation. They also demonstrate why a formal bioequivalence judgment requires the prespecified criterion and analysis details, not simply a comparison of point estimates.

Finally, the record distinguishes endpoint participants from participants listed in the safety results but does not explain the differing counts. Recognizing such reporting limits is part of sound statistical interpretation. The available information is enough to describe the principal estimates and their uncertainty, but not enough to reconstruct all aspects of the trial analysis or make broader clinical claims.

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 describe the randomization procedure, treatment sequence, timing between treatments, or period-specific conduct. These details can be relevant in a crossover study. It also does not report participant-level paired observations, so the relationship between each participant’s measurements across treatments cannot be evaluated from the posted summaries.

The sponsor’s analysis method is not reported, and the record does not give the decision bounds for the bioequivalence assessment. The reported geometric-mean ratio and 90% confidence interval can therefore be stated, but a formal conclusion about whether a specified criterion was satisfied cannot be independently assessed from the registry entry. The recalculated arithmetic mean difference is unadjusted and should not be treated as a reconstruction of the sponsor’s crossover analysis.

The registry records enrollment of 80 and lists 76 participants per group for the primary endpoint, but does not explain the difference. It states that all participants who completed the study had their samples analyzed, yet does not provide the number who completed the study, participant flow, reasons for missing observations, or missing-data methods. The safety results list 80 participants at risk in each group; the record does not explain how those counts relate to the endpoint population.

Six outcome measures and six analyses are listed, but secondary results are not posted in the record described. The multiplicity strategy, if any, is not reported. The original sample-size justification and original analysis assumptions are also not reported. The planning illustration is separate from those original design decisions.

Finally, the study evaluates Cmax in healthy, adult, non-smoking subjects under non-fasting conditions. The registry does not post other outcome results or information that would support generalization to other populations, settings, or clinical outcomes. These are limits on what the record can establish, not evidence that an unreported procedure or result did or did not occur.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Losartan Potassium/Hydrochlorothiazide 100/25 mg Tablets in Healthy Subjects Under Non-Fasting Conditions — NCT01149473.
• Registry record last updated 2024-08-20; status last verified 2024-08.
• Results first posted 2010-09-14.
• 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

NCT01149473 is a completed phase 1 randomized, open-label crossover study sponsored by Teva Pharmaceuticals USA. Its recorded start was 2004-03, with primary completion in 2004-04. The registry lists 80 enrolled healthy subjects and compares losartan potassium/hydrochlorothiazide 100/25 mg tablets with Hyzaar® 100/25 mg tablets under non-fasting conditions.

The primary endpoint is losartan Cmax, measured in ng/mL using blood samples collected over a 48 hour period. The reported group means are 458.3 for the test product and 409.3 for the reference product, with 76 participants listed in each group. The recalculated mean difference is 48.97, with a 95% confidence interval from -43.18 to 141.1 and an unadjusted p-value of 0.298. The sponsor’s posted geometric-mean ratio is 109, with a 90% confidence interval from 98.1 to 120.

The registry does not report the sponsor’s analysis method, bioequivalence decision bounds, original sample-size rationale, or full details of missing-data and multiplicity procedures. The posted results support interpretation of the measured endpoint and its uncertainty, with those reporting limits in view.