Losartan Potassium/Hydrochlorothiazide 100/25 mg Tablets in Healthy Subjects Under 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 Fasting Conditions (NCT01149486), a randomized phase 1 study. The primary outcome is Cmax of Losartan(Maximum Observed Concentration of Drug Substance in Plasma).

2. Clinical Question

Relative bioavailability concerns the rate and extent of absorption of a medicine. Comparing the test tablet with the reference under the same fasting conditions allows the study to describe whether the measured drug exposure differed between products in this study population. Because the design was a crossover, participants received both study products, although the sequence, period structure, and washout details are not reported in the registry record. The posted results therefore support a comparison of measured concentrations and exposure summaries, but interpretation of the sponsor analysis depends on its reported ratio and confidence interval, not simply on the raw arithmetic means.

3. Trial Design

This was a randomized, unmasked, phase 1 crossover study of two oral products in healthy subjects. The registry record lists 20 participants enrolled and describes the study as completed. The products were losartan potassium/hydrochlorothiazide 100/25 mg tablets and Hyzaar® 100/25 mg tablets. Each was studied as a single oral dose under fasting conditions. The study objective was relative bioavailability: comparing the rate and extent of absorption of the Teva product with the reference product.

A crossover design means that participants receive more than one intervention at different points in the study, allowing measurements under the different treatments to be compared within participants. Randomization can be used to assign the order of treatments, but the sequence allocation and its implementation are not reported in the registry record. The registry also does not report the number or length of treatment periods, washout duration, or details of the blood-sampling schedule beyond collection over a 48 hour period. Masking is listed as none.

The primary endpoint was losartan Cmax, reported as a continuous measure in ng/mL. The registry states that samples from all participants who completed the study were analyzed. The arm summaries list 19.0 participants for each product. The number of participants completing the study, reasons for any missing endpoint data, and a participant flow account are not reported in the registry record. Three secondary measures concern the losartan carboxy acid metabolite: Cmax, AUC0-t, and AUC0-inf.

Although the design is crossover, the posted arm-level means and standard deviations do not supply the within-participant covariance needed to reconstruct a paired analysis from those summaries alone. The simple recalculations therefore describe unadjusted comparisons of the posted arm summaries; they are not a substitute for a crossover analysis using participant-level data. The registry lists the sponsor's geometric-mean ratio analysis separately. Detailed protocol and analysis-plan information, including any prespecified treatment of periods or sequences, is 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

Reasons for not completing this period:

Washout of 7 Days

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 was Cmax of losartan: the maximum observed concentration of the drug substance in plasma, measured in ng/mL. Blood samples were collected over a 48 hour period. Cmax is a concentration-based measure, describing the peak observed plasma level after dosing. In a relative bioavailability study, it is used to compare the peak exposure following the test product with the peak exposure following the reference product.

The registry describes the endpoint as a mean with standard deviation and states that bioequivalence was based on losartan Cmax. The sponsor's posted analysis expresses the comparison as the test-to-reference geometric-mean ratio multiplied by 100 and gives a 90% confidence interval. The registry record does not report the acceptance bounds used for judging bioequivalence or the detailed statistical model used to obtain that ratio and interval.

As a general statistical point, peak concentration is one component of drug exposure. It does not by itself describe the full concentration-time profile; area-under-the-curve measures address overall exposure over a stated interval. The registry posts three such metabolite-related secondary endpoints, but the primary question is specifically about losartan Cmax. Conclusions about that endpoint should therefore be kept distinct from conclusions about total exposure or the metabolite endpoints.

7. Results Posted in the Registry

• Losartan/HCTZ (Test): mean 509.63 versus 538.11 on control; difference -28.48 (95% CI -223.65 to 166.69), standardized effect d = -0.09; z-test p = 0.775.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Cmax of Losartan Carboxy Acid(Maximum Observed Concentration of Drug Substance in Plasma)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Losartan/HCTZ (Test): mean 726.85 versus 675.54 on control; difference 51.31 (95% CI -78.49 to 181.11), standardized effect d = 0.25; z-test p = 0.438.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Losartan/HCTZ (Test) and the control. The interval gives the range of effects that remain compatible with the data.

AUC0-t of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Losartan/HCTZ (Test): mean 4,237 versus 4,117 on control; difference 119.71 (95% CI -600.68 to 840.10), standardized effect d = 0.11; z-test p = 0.745.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Losartan/HCTZ (Test) and the control. The interval gives the range of effects that remain compatible with the data.

AUC0-inf of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Infinity)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Losartan/HCTZ (Test): mean 4,281 versus 4,165 on control; difference 116.70 (95% CI -608.55 to 841.95), standardized effect d = 0.10; z-test p = 0.752.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Losartan/HCTZ (Test) and the control. The interval gives the range of effects that remain compatible with the data.

The three posted secondary outcomes concern losartan carboxy acid, a metabolite: its maximum observed concentration, its area under the concentration-time curve from time zero to the last measurable concentration, and its area under the curve from time zero to infinity. Taken together, the sponsor-reported geometric-mean ratios are on either side of 100 and their 90% confidence intervals include 100. The recalculated arithmetic mean-difference intervals also include zero. Across these measures, the posted analyses therefore do not locate the metabolite comparison with high precision.

This broad pattern is related to, but distinct from, the primary result. The primary endpoint measures losartan Cmax; the secondary measures concern the carboxy acid metabolite and include both peak concentration and exposure over time. The secondary findings add information about the measured metabolite profile, but they do not replace the primary endpoint or directly answer its question. Their interpretation also depends on the separate methods and uncertainty ranges used for each outcome.

As a general statistical explanation, testing multiple outcomes creates more opportunities for chance findings if each is assessed independently. Adjustments or a prespecified hierarchy can help control the interpretation of multiple comparisons, but neither a multiplicity plan nor an adjustment method is reported in the registry record. The secondary analyses should consequently be treated as supportive or exploratory rather than as independent confirmation. Their unadjusted p-values in the recalculations do not account for the number of outcomes considered.

The registry lists nine outcome measures and nine analyses overall, but the posted secondary endpoint information covers three measures. Details for the other listed measures are not reported in the registry record. No new combined estimate across the secondary outcomes can be inferred from the separate summaries. The most defensible reading is that the available metabolite results show no sharply resolved difference on the reported scales, while the precision and multiplicity limitations constrain how strongly these results can be interpreted.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Cmax of Losartan Carboxy Acid(Maximum Observed Concentration of Drug Substance in Plasma)
• AUC0-t of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
• AUC0-inf of Losartan Carboxy Acid(Area Under the Concentration-time Curve From Time Zero to Infinity)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: losartan Cmax in ng/mL. The registry reports a mean and standard deviation for each product. The mean is the arithmetic average of the observed values, while the standard deviation describes how dispersed individual observations are around that average. A standard deviation is not the uncertainty in the mean itself; the uncertainty in an estimated mean also depends on the number of observations and on the study design.

What does the unadjusted mean difference represent?

The recalculated mean difference compares the test-product mean with the reference-product mean on the original concentration scale. For the primary outcome, the estimate is -28.48 ng/mL. Negative values indicate a lower arithmetic mean in the test arm than in the reference arm under the stated subtraction convention. Its 95% confidence interval, -223.7 to 166.7, includes zero. The associated unadjusted p-value is 0.775. These figures summarize an unadjusted comparison based on posted group summaries, rather than the sponsor's geometric-mean ratio analysis.

As a general explanation, a p-value measures how compatible the observed data are with a specified null hypothesis under the assumptions of the test. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of a difference. A large p-value does not demonstrate that two products are equivalent. A conventional difference test asks whether the data give evidence against a zero difference; an equivalence analysis instead asks whether the plausible differences are confined within prespecified acceptable bounds.

Why distinguish the crossover analysis from the recalculation?

In a crossover study, each participant receives both products, so treatment comparisons can use the within-participant relationship between the observations. That relationship can affect the standard error and the confidence interval. The posted arm means and standard deviations do not include the within-person covariance or participant-level data. Consequently, the simple recalculation is not a reconstruction of a paired crossover model. The detailed sponsor model, including any handling of treatment sequence and period, is not reported in the registry record.

This limitation is especially relevant when interpreting the recalculated interval and p-value. They are useful as transparent, unadjusted summaries of the posted data, but they may not reproduce the sponsor's design-aware analysis. No discrepancy is flagged between the posted summary and the recalculated summaries. The two analysis types should nonetheless remain clearly distinguished because they use different scales and statistical information.

What does the sponsor's ratio describe?

The sponsor reports the ratio of the test-to-reference geometric means multiplied by 100. The primary estimate is 93.45, with a 90% confidence interval from 80.20 to 108.88. A geometric-mean ratio is a relative-scale comparison, rather than an additive difference in ng/mL. As a general statistical explanation, geometric means are commonly used for positive measurements whose variation is more naturally considered on a multiplicative scale. The registry does not provide the transformation, model, or other computational details, so the specific procedure behind this estimate is not reported in the registry record.

The confidence interval represents a range of values compatible with the data and analysis under the method's assumptions. For the ratio, 100 is the value representing equal geometric means. The interval includes values below and above 100, indicating that the posted estimate is not perfectly precise about the relative difference. Whether this interval meets an equivalence criterion depends on bounds set in advance; the bounds are not reported in the registry record.

How should standard deviations and effect sizes be read?

The posted standard deviations describe variability in observed concentrations among participants. The recalculation also reports a pooled standard deviation and a standardized effect estimate. A standardized effect expresses the mean difference relative to a measure of variability, allowing effects on different measurement scales to be compared in broad terms. These are recalculation summaries, not additional sponsor findings. The crossover covariance is not represented in these group-level calculations.

As a general statistical point, a small estimated effect does not guarantee precise estimation. Precision depends on both the amount of variability and the amount of information in the analysis. Here the confidence interval for the raw-scale comparison is wide relative to the point estimate. That breadth cautions against treating the point estimate as a highly precise measure of the underlying difference.

The registry does not report a prespecified primary-analysis model, missing-data method, interim analysis plan, or multiplicity strategy. The record also does not report the original sample-size justification. These are distinct from the stated planning illustrations, which use an effect based on the observed data and specified assumptions. They should not be interpreted as the trial's original design plan.

11. Confidence Intervals and Precision

Precision concerns how narrowly the data and analysis locate an estimated effect. The sponsor's primary geometric-mean ratio is 93.45, and its 90% confidence interval ranges from 80.20 to 108.88. The interval includes 100, the relative-scale value corresponding to equal geometric means, and extends on either side of that value. The estimate therefore has meaningful uncertainty about the magnitude and direction of the relative difference. The registry does not report equivalence margins, so the interval cannot be assessed against a stated acceptance range.

The unadjusted raw-scale mean difference is -28.48 ng/mL, with a 95% confidence interval from -223.7 to 166.7. Because the interval includes zero and covers both negative and positive values, the recalculated arithmetic comparison is also imprecise about the direction and size of the difference. The unadjusted p-value of 0.775 should be read alongside this interval, not as proof of sameness.

As a general explanation, a confidence interval is an uncertainty range produced by a statistical method. Under repeated use of the same method and its assumptions, intervals at a stated confidence level would cover the fixed parameter at the corresponding long-run rate. It is not a probability statement that the particular parameter lies in the realized interval. A narrower interval generally indicates greater precision, while a wider interval leaves more plausible values compatible with the analysis.

The sponsor's ratio interval and the recalculated mean-difference interval are not directly interchangeable: they use different scales, confidence levels, and analysis approaches. The recalculation is based on posted arm summaries and does not capture within-participant crossover covariance. The sponsor method details are not reported in the registry record. Both intervals should therefore be interpreted within the analysis that produced them, without treating either as a definitive statement about all possible settings or populations.

12. 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 estimates are illustrations based on the observed effect, not the original enrollment plan. For these continuous outcomes, the figures are participants per arm, not total events. The stated 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 set to the stated fraction of the observed effect. The registry record does not report the original sample-size justification or the assumptions used when the trial was designed.

The 80% power column gives the illustrative participants per arm under the stated assumptions for a design with an 80% chance of detecting the specified effect if that effect were the true one. The 90% power column applies the same idea with a higher target chance of detection. Higher target power generally requires more participants when the other assumptions are unchanged. These figures should be read as planning aids, not as observed properties of the completed study.

The planning illustrations include scenarios for 100%, 75%, and 50% of the observed effect. A smaller target effect is harder to distinguish from background variability, so the stated calculations require more participants per arm for the smaller-effect scenarios. The estimates are sensitive to the observed effect used as their starting point. In a small study, that observed effect may itself be uncertain, so the illustrations should not be treated as a definitive sample-size recommendation.

These calculations are not observed power. They do not tell whether the completed trial had a particular probability of finding a result, and they do not establish that an inconclusive comparison reflects equivalence. The original design assumptions, any planned allowance for missing observations, and any crossover-specific sample-size calculations are not reported in the registry record.

13. 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 = -28.480; pooled standard deviation σ = 306.922.
2. n = 2 × (1.96 + 0.842)² × 306.922² / -28.480² = 1,823.1, rounded up to 1,824 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 <- -28.48                      # observed difference in means
sigma <- 306.922461380721                     # 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(1149486)
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 = 1,824 (80% power), 2,441 (90% power)
 75% of observed effect: n per arm = 3,242 (80% power), 4,339 (90% power)
 50% of observed effect: n per arm = 7,293 (80% power), 9,763 (90% power)
power.t.test: 1824.1 
Simulated power at n = 1,824 per arm: 0.799 (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.

14. Analyses Reported by the Sponsor

The sponsor's posted primary analysis is a test-to-reference geometric-mean ratio multiplied by 100, estimated as 93.45, with a 90% confidence interval from 80.20 to 108.88. This is the registry's reported ratio-scale analysis for losartan Cmax. The method used to obtain the ratio and interval is not reported in the registry record, and the record does not state the acceptance bounds for a formal bioequivalence assessment.

The recalculation uses the posted arithmetic means and standard deviations to estimate an unadjusted mean difference of -28.48 ng/mL, with a 95% confidence interval from -223.7 to 166.7 and an unadjusted p-value of 0.775. It is not a reproduction of the sponsor's geometric-mean ratio. It uses a different effect scale and does not incorporate within-participant covariance from the crossover design, which is not available in the posted arm summaries.

The calculations are not flagged as discrepant. Even so, the sponsor's analysis and the recalculation should not be treated as interchangeable tests. The sponsor's posted ratio is the registry's reported analysis; the recalculation is a supplementary unadjusted comparison. A nonsignificant difference test does not establish equivalence, and the ratio cannot be judged against formal acceptance limits that are not reported. The detailed sponsor analysis plan and model are not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity adjustment, a prespecified hierarchy among outcomes, or a strategy for interpreting the family of primary and secondary analyses. This matters because repeated testing can increase the chance of at least one apparently notable result arising by chance. The three posted secondary outcomes each describe a different aspect of losartan carboxy acid, and the record lists nine outcome measures and nine analyses overall. Without a stated plan, the secondary findings should be interpreted cautiously and should not be treated as though they were a single confirmatory test.

The record identifies losartan Cmax as the primary endpoint and lists the three carboxy acid measures as secondary outcomes. It does not report whether additional endpoints were designated in the protocol, whether analyses were prespecified in a hierarchy, or how any missing endpoint data were handled. The stated analysis population includes participants who completed the study and had their samples analyzed. Participant flow, reasons for missing data, and the number of people excluded from each analysis are not reported in the registry record.

The posted arm summaries include 19.0 participants for each treatment, while enrollment is listed as 20. The registry does not provide a detailed account of completion or explain the relationship between enrollment and the analyzed endpoint population. It also does not report imputation, sensitivity analyses, or other missing-data procedures. This limits assessment of whether missing observations could have influenced the estimates.

The original sample-size justification and any interim-analysis plan are not reported in the registry record. Those omissions do not negate the posted estimates, but they restrict evaluation of the trial's planned precision and decision rules. The sample-size illustrations based on observed effects are not evidence of the original design plan. The analysis information available is therefore sufficient to describe the posted outcomes, but not to reconstruct all protocol-level decisions or evaluate their implementation.

16. 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.

Most frequent non-serious adverse event terms

The posted serious adverse event figures report zero participants with serious adverse events among 20 at risk for the test product and zero among 20 at risk for the reference product. These figures describe the registry's serious-event counts for this study. They do not establish that no other adverse events occurred: the registry separately reports other adverse events affecting 3 participants for the test product and 6 for the reference product.

The safety information is limited to these aggregate counts. Serious-event terms are not listed, and deaths are not reported in the registry record. The registry does not provide event-level descriptions, timing, severity classifications for the other events, or an assessment of whether events were considered related to treatment. The short description of the study as a single-dose, fasting-condition comparison in healthy subjects also defines the context of these counts; the record does not support broader safety conclusions beyond the observations posted for this study.

As a general statistical point, zero observed serious events in a small study does not establish that the underlying risk is zero. The counts are descriptive, and the registry does not report a comparative safety analysis or confidence intervals for adverse-event differences. The figures should therefore be read as observed counts in the listed groups, not as proof of equal safety or as a prediction of event rates in other populations or circumstances.

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

The results describe relative bioavailability measurements after a single oral dose of the test and reference products under fasting conditions in healthy adults. For the primary endpoint, the sponsor reported a geometric-mean ratio of 93.45 and a 90% confidence interval from 80.20 to 108.88. The recalculated arithmetic comparison gave a mean difference of -28.48 ng/mL, with a 95% confidence interval from -223.7 to 166.7. These estimates describe the observed study data with uncertainty; they do not by themselves settle a formal equivalence question.

As a general statistical principle, demonstrating equivalence requires a prespecified margin and an analysis showing that the relevant confidence interval lies within that margin. The acceptance bounds are not reported in the registry record. A nonsignificant test for a difference, such as the unadjusted p-value of 0.775, is not proof that two products are equivalent. Likewise, a ratio estimate near 100 does not alone establish a formal bioequivalence conclusion when its interval and decision bounds must both be considered.

The study concerns pharmacokinetic measurements, not clinical outcomes. It does not establish effects on symptoms, disease outcomes, or longer-term use. Participants were healthy subjects, the products were administered as a single dose, and the conditions were fasting. Findings cannot automatically be extended to other populations, dosing patterns, or conditions. The registry record does not report results for those settings.

The recalculated raw-scale comparison is an unadjusted analysis of arm-level summaries and does not recover the within-participant relationship inherent in a crossover design. The sponsor's detailed analysis method is not reported. Thus, the most appropriate interpretation is bounded: the record reports a relative concentration estimate and its uncertainty for this study, alongside unadjusted summaries, but does not provide all details needed to independently reproduce or formally adjudicate the sponsor's bioequivalence analysis.

The adverse-event counts are also limited observations from this study. Zero serious adverse events were reported in either group, while other adverse events were reported in both. The small, short-term study record does not establish that serious events cannot occur or characterize risks outside the observed setting. These results should be understood as statistical findings from one completed study, not as treatment advice or a general claim about clinical effects.

18. Why This Trial Matters Statistically

This trial is statistically useful because it illustrates the difference between a relative bioavailability analysis and a simple comparison of arithmetic means. The sponsor reports a test-to-reference geometric-mean ratio with a 90% confidence interval, while the summary-statistic recalculation gives an unadjusted mean difference with a 95% confidence interval. Those statistics use different scales and answer related but distinct questions. Reading them as interchangeable would obscure what each estimate represents.

The crossover design also highlights an important issue in interpreting aggregate results. A within-participant comparison can use information about how each person's measurements under the two products relate. Arm-level means and standard deviations alone do not retain that covariance. The recalculation is transparent about the posted group summaries, but it cannot recreate a participant-level crossover analysis. This is a practical reminder that design details and analysis methods matter when interpreting standard errors and confidence intervals.

The study also shows why a nonsignificant difference test should not be equated with evidence of equivalence. The primary unadjusted p-value is 0.775, but formal equivalence requires a defined margin and an interval assessed against that margin. The acceptance bounds and detailed sponsor method are not reported in the registry record. Precision is therefore central: the point estimate alone does not capture the range of values compatible with the reported analysis.

Finally, planning calculations based on an observed effect are not the same as the original sample-size rationale and are not observed power. Their interpretation depends on assumptions and on the effect used as a planning target. Keeping these distinctions explicit helps clinical researchers separate descriptive findings, confirmatory decisions, and prospective planning.

19. 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 leaves important design and analysis details unreported. Although the study is described as randomized and crossover, the treatment sequence, period structure, washout, and sequence-generation procedures are not reported. The sponsor's detailed statistical model and the handling of period or sequence effects are also not reported. These omissions limit independent assessment of how the crossover design was incorporated into the primary analysis.

The registry states that samples from participants who completed the study were analyzed, and each posted arm summary includes 19.0 participants; enrollment is 20. A participant-flow account, reasons for missing data, and missing-data methods are not reported. The original sample-size justification, any interim analyses, and a multiplicity plan are also not reported. Consequently, the posted planning illustrations should not be mistaken for the original design rationale, and the secondary analyses should be interpreted cautiously.

The formal bioequivalence acceptance limits are not reported, nor is the method underlying the sponsor's geometric-mean ratio and confidence interval. The raw-scale recalculation is based on summary statistics and does not use within-participant covariance. It therefore cannot serve as a complete independent reanalysis of a crossover trial. The registry also reports a 48 hour blood-sampling period but does not provide detailed sampling times in the information available.

Generalizability is limited by the stated study context: healthy subjects, a single oral dose, and fasting conditions. The registry does not report results for repeated dosing, fed conditions, or participants with a clinical condition. Safety reporting is aggregate; event terms for serious events are not listed, and deaths are not reported in the registry record. These limitations constrain what can be inferred from the posted pharmacokinetic and adverse-event summaries.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Losartan Potassium/Hydrochlorothiazide 100/25 mg Tablets in Healthy Subjects Under Fasting Conditions — NCT01149486.
• Registry record last updated 2010-12-08; status last verified 2010-11.
• 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.

23. Record Summary

The registry describes a completed, randomized, unmasked phase 1 crossover study comparing Teva losartan potassium/hydrochlorothiazide 100/25 mg tablets with Hyzaar® 100/25 mg tablets. The study enrolled 20 healthy subjects and evaluated a single oral dose under fasting conditions.

The primary endpoint was losartan Cmax, measured in ng/mL from blood samples collected over a 48 hour period. The sponsor reported a test-to-reference geometric-mean ratio of 93.45 with a 90% confidence interval from 80.20 to 108.88. An unadjusted recalculation from posted arm summaries estimated a mean difference of -28.48 ng/mL, with a 95% confidence interval from -223.7 to 166.7 and p = 0.775.

Three secondary outcomes describe losartan carboxy acid concentrations and exposure. The record reports zero serious adverse events in both groups and other adverse events affecting 3 participants with the test product and 6 with the reference. Formal bioequivalence limits, detailed analysis methods, missing-data procedures, and original sample-size assumptions are not reported in the registry record.