Clinical Efficacy Study of Salmeterol Xinafoate/Fluticasone Propionate in Asthma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clinical Efficacy Study of Salmeterol Xinafoate/Fluticasone Propionate in Asthma (NCT02260492), a randomized phase 1 study. The primary outcome is Area Under the Serial FEV1-time Curve (AUC 0-12h).

2. Clinical Question

FEV1 is a measure of lung function. In this study, the serial measurements were collected before dosing and at multiple post-dose times during the first 12 hours on Day 1. Summarizing the measurements as an area under the curve captures the pattern across that interval rather than relying on a single measurement time. The registry record’s description identifies bioequivalence of lung function as the goal of the primary endpoint assessment. The equivalence margin and the detailed decision rule used for that assessment are not reported in the registry record.

3. Trial Design

The registry record describes a randomized, quadruple-masked, parallel-group study with phase listed as Phase 1. The study status is completed. It began in 2014-09, and primary completion was recorded in 2015-05. Total enrollment is listed as 879. The sponsor is Oriel Therapeutics, and the condition studied was asthma.

Three treatment groups are listed: OT329 Solis, Advair Diskus, and placebo. Each was administered by inhalation twice daily throughout the study. The two active products contain fluticasone propionate and salmeterol xinafoate. The study summary states that the purpose was to establish equivalence between OT329 Solis and Advair Diskus. The placebo group is also included in the posted primary endpoint results, but the registry record does not state in the available description how the placebo comparison was intended to support the active-treatment comparison.

For the primary endpoint, the population is identified as intent-to-treat. The endpoint results list 418 participants in the OT329 Solis group, 419 in the Advair Diskus group, and 42 in the placebo group. These endpoint counts do not add up to the enrollment total as recorded, and the reason is not reported in the registry record. The study record does not provide the details of randomization procedures, masking procedures, treatment duration beyond the twice-daily study regimen, or the protocol’s sample-size justification. It also does not report the original assumptions used to plan enrollment.

Three outcome measures and two analyses are listed in the results information. The primary endpoint is the FEV1 area-under-the-curve measure. The listed secondary outcome is the number of participants with adverse events. The registry record does not describe the two analyses in enough detail to establish whether every outcome measure had a posted result or how each analysis related to the planned statistical strategy.

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.

Before assignment: 647 Failed screening (42%) * 239 failed because they did not have 40-85% pred FEV1 * 240 failed because they were not \>15% reversible with albuterol * 168 failed for other inclusion/exclusion criteria

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent-to-treat (ITT)

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.

Population: Intent-to-Treat (ITT)

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Serial FEV1-time Curve (AUC 0-12h), measured over 0-12 hours after dosing on Day 1.

The primary endpoint is the area under the serial FEV1-time curve from 0 to 12 hours after dosing on Day 1, measured in liters. It summarizes repeated lung-function measurements collected before dosing and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after dosing. The endpoint description characterizes the comparison as a bioequivalence assessment of lung function over the 12-hour period following the first dose.

An area-under-the-curve measure uses information across multiple measurement times. In general, this can describe the overall pattern of a continuous outcome during a defined interval, rather than emphasizing a single time point. It is useful when the study question concerns a response over time. Its interpretation depends on how the measurement is constructed and on the comparison specified in the analysis.

The registry reports group means and standard deviations for this continuous endpoint. The sponsor’s reported comparison is an ANCOVA test/reference ratio for OT329 Solis relative to Advair Diskus, while the recalculated comparisons in the posted results compare each active group’s mean with placebo. Those analyses answer different questions. The record labels the sponsor analysis as equivalence but does not report the equivalence margin or the full analysis specification. The endpoint results therefore need to be read alongside the exact comparison and method used, not as if every reported contrast represented the same treatment question.

7. Results Posted in the Registry

• OT329 Solis: mean 29.61 versus 27.27 on control; difference 2.34 (95% CI -0.15 to 4.83), standardized effect d = 0.26; z-test p = 0.065.
• Advair Diskus: mean 30.15 versus 27.27 on control; difference 2.88 (95% CI 0.39 to 5.37), standardized effect d = 0.32; z-test p = 0.023.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports two different kinds of comparison for the primary endpoint. Keeping those analyses distinct is central to interpreting the results. The sponsor’s analysis is an adjusted comparison of the two active treatments, while the posted recalculations are simple unadjusted contrasts of each active treatment against placebo. The contrast, method, and reference group determine what an estimate means.

What does a mean difference describe?

A mean difference expresses how far apart two group averages are, in the units of the measured outcome. For this endpoint, those units are liters. The recalculated OT329 Solis-placebo estimate is 2.34, and the Advair Diskus-placebo estimate is 2.881. These estimates use the group means and standard deviations posted for the endpoint. They are unadjusted calculations, not the sponsor’s ANCOVA result. An estimate alone does not convey its uncertainty, so it is read together with its confidence interval.

The record gives mean endpoint values of 29.61 for OT329 Solis, 30.15 for Advair Diskus, and 27.27 for placebo. The corresponding standard deviations are 9.044, 9.107, and 7.71. In general, a standard deviation describes variation among observations around a group mean. It is not the standard error of the group mean and is not a confidence interval. A standard error describes uncertainty in an estimated quantity, while a confidence interval gives a range of values compatible with the estimate and its statistical uncertainty under the analysis assumptions.

What does the ANCOVA ratio represent?

The sponsor’s analysis is reported as an ANCOVA test/reference ratio. ANCOVA is a method that compares group outcomes while accounting for covariates included in the model. The registry does not identify the covariates, the model specification, or the treatment of missing observations. The reported ratio is 1.080, with a 90% confidence interval from .8 to 1.25. This is an adjusted active-treatment comparison and is not interchangeable with a difference between the unadjusted group means or with either contrast against placebo.

The record identifies the sponsor analysis as an equivalence analysis. In general, an equivalence analysis asks whether the treatment contrast is sufficiently contained within prespecified bounds around an agreed comparison value. Those bounds, often called equivalence margins, need to be known to assess the decision. They are not reported in the registry record. The record’s label and reported result can therefore be described, but readers cannot reconstruct the complete equivalence criterion from the entry.

How should p-values be read?

A p-value describes how compatible data are with a specified null hypothesis under a particular statistical model. It is not the probability that a treatment effect is true, nor does it express the size or clinical importance of an effect. For the unadjusted active-versus-placebo calculations, the reported p-values are 0.065 for OT329 Solis and 0.023 for Advair Diskus. These p-values relate to those specific recalculated contrasts, not to the sponsor’s active-treatment equivalence question. The sponsor analysis reports p <0.05, but the registry does not give enough detail to interpret that value as a standalone equivalence decision.

In general, a two-sided significance threshold of 0.05 is used in the planning illustration recorded for the sample-size calculations. This does not establish that the trial’s original analysis plan used the same threshold. The original protocol’s statistical plan is not reported in the registry record.

Why does over-dispersion matter?

In general, over-dispersion means that observed variability is greater than a statistical model expects. For a continuous endpoint, the spread of observations affects standard errors and the precision of estimates. The reported standard deviations give a direct indication of variation in this endpoint, but the registry does not state that over-dispersion was assessed or that a model assumed a particular dispersion pattern. No conclusion about such a model feature should be inferred from these summary statistics alone.

What does the recalculation add?

The unadjusted recalculations provide a transparent way to read the posted group summaries as active-treatment-versus-placebo mean differences, confidence intervals, and p-values. They do not adjust for covariates and do not estimate the same contrast as the sponsor’s test/reference ratio. The record flags a discrepancy, so the sponsor’s own analysis takes precedence when describing the sponsor’s equivalence question. The recalculations can still serve as descriptive context, provided their different reference group and method are stated clearly.

10. Confidence Intervals and Precision

A confidence interval describes uncertainty around an estimated quantity under the assumptions of the analysis. It is not a range containing a fixed proportion of individual participants’ measurements, and it does not guarantee that the true value falls inside the interval. Wider intervals indicate less precision; narrower intervals indicate greater precision for the estimate under the same framework.

For OT329 Solis compared with placebo, the recalculated mean difference is 2.34 liters, with a 95% confidence interval from -0.148 to 4.828. For Advair Diskus compared with placebo, the recalculated mean difference is 2.881 liters, with a 95% confidence interval from 0.392 to 5.37. The first interval includes zero, whereas the second does not. The endpoints describe uncertainty for these unadjusted contrasts, not the sponsor’s active-treatment comparison.

The sponsor’s ANCOVA result is reported as a test/reference ratio of 1.080 with a 90% confidence interval from .8 to 1.25. It is a different estimand and uses a different confidence level from the recalculated placebo contrasts. Its interval must be interpreted in the context of the sponsor’s equivalence framework. The equivalence bounds and detailed analysis plan are not reported in the registry record, so the interval alone is not enough to independently verify the decision criterion.

Precision also depends on the amount of information in each group and the outcome’s variability. The placebo endpoint group has 42 participants, compared with 418 for OT329 Solis and 419 for Advair Diskus. The standard deviations are 7.71, 9.044, and 9.107, respectively. Those features help explain why interval width cannot be understood from the point estimate alone. The record does not provide participant-level data or additional model details that would support a deeper assessment of precision.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not a record of the trial’s original enrollment rationale. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect targeted is the stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

For the mean-difference comparisons in this analysis, the figures are participants per arm, not total events. The entries distinguish planning for 100%, 75%, and 50% of the observed effect. For example, planning for 75% of the observed effect requires more participants per arm than planning for the full observed effect. Planning for 50% requires more again. Smaller effects are harder to distinguish from random variation, so they generally require more participants to achieve the same target power.

The 80% power column gives the planned number of participants per arm under the stated assumptions for an 80% chance of detecting the specified effect if that effect is present and the model assumptions hold. The 90% power column gives the corresponding planning target for a 90% chance. These values are hypothetical planning quantities, not evidence about the probability that the completed trial found a real effect. This is not observed power.

The estimates are based on the observed effect in the posted recalculation, which itself is uncertain. They should therefore be read as illustrations of how required sample size changes with the targeted effect, rather than as a replacement for a prospective design calculation. The registry record does not report the assumptions used to determine the actual enrollment of 879.

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 = 2.340; pooled standard deviation σ = 8.933.
2. n = 2 × (1.96 + 0.842)² × 8.933² / 2.340² = 228.8, rounded up to 229 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 <- 2.34                      # observed difference in means
sigma <- 8.93270320166762                     # 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(2260492)
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 = 229 (80% power), 307 (90% power)
 75% of observed effect: n per arm = 407 (80% power), 545 (90% power)
 50% of observed effect: n per arm = 916 (80% power), 1,225 (90% power)
power.t.test: 229.7 
Simulated power at n = 229 per arm: 0.797 (20000 replicates)

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

13. Analyses Reported by the Sponsor

The sponsor’s analysis addresses the stated active-treatment comparison: OT329 Solis relative to Advair Diskus. It uses ANCOVA and reports a test/reference ratio of 1.080, a 90% confidence interval from .8 to 1.25, p <0.05, and an equivalence classification. This is the analysis to use when describing the sponsor’s own equivalence result.

The simple recalculations are different. They compare each active group with placebo using unadjusted mean differences. Their estimates are 2.34 for OT329 Solis versus placebo and 2.881 for Advair Diskus versus placebo. They do not reproduce the sponsor’s adjusted test/reference ratio, and they do not test the same treatment contrast.

The registry record flags a discrepancy between the sponsor’s analysis and the recalculation. The sponsor’s own analysis takes precedence for the sponsor’s stated question. The specific reason for the discrepancy is not reported in the registry record, so it should not be attributed to a particular modeling choice or data-handling decision. The methods and reference groups are visibly different, but the record does not establish that these differences fully explain the discrepancy. The sponsor’s equivalence bounds and detailed ANCOVA specification are also not reported, limiting independent evaluation of the result.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures and two analyses, and identifies the number of participants with adverse events as a secondary outcome. The record does not provide enough detail to determine how all listed measures relate to the reported analyses, whether additional outcomes were planned, or whether the posted results cover every planned outcome. The full statistical analysis plan is not reported in the registry record.

Multiplicity arises when multiple outcomes, comparisons, time points, or analysis choices are assessed. In general, conducting multiple tests can increase the chance of finding at least one statistically notable result by chance if no adjustment or other prespecified strategy is used. Whether that concern applies, and how it was handled, depends on the complete analysis plan. The registry does not report a multiplicity adjustment, a hierarchical testing strategy, or whether any such approach was prespecified. No claim about the presence or absence of a correction can be made from the listed results alone.

The primary endpoint population is described as intent-to-treat. The record does not explain how the ITT population was defined, whether all randomized participants were included in the primary analysis, or how missing endpoint observations were handled. It does not report the number of participants with missing primary endpoint data, reasons for missingness, imputation methods, or sensitivity analyses. These details matter because missing-data methods can affect both the estimate and its uncertainty, particularly when missingness differs among groups or relates to the outcome.

The posted adverse-event group counts also do not exactly match the primary endpoint group counts. The record does not explain the population definitions behind the two sets of counts. It would be inappropriate to assume a particular analysis population or reason for the difference.

The record reports that the primary endpoint was assessed using an ANCOVA for the sponsor’s active-treatment comparison, but does not identify the covariates, model diagnostics, analysis population details beyond the endpoint’s ITT label, or handling of protocol deviations. It also does not report interim analyses or stopping rules. These omissions limit assessment of how the analysis was specified and whether the posted results reflect the original plan. They do not establish that any particular procedure was or was not used.

15. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myocardial infarction (0.2%), h. pylori infection (0.2%).

The registry reports serious adverse events for the treatment groups. In the OT329 Solis group, 417 participants were listed as at risk and 0 had a serious adverse event. In the Advair Diskus group, 419 were listed as at risk and 2 had a serious adverse event. In the placebo group, 43 were listed as at risk and 0 had a serious adverse event. The record also lists 1 death in the Advair Diskus group and 0 in each of the other groups. These figures describe the posted counts; the record does not state that the death was related to treatment.

The two serious-event terms listed are Myocardial Infarction and H. pylori infection, each reported as 0.2%. The registry record does not provide further details in the listed information about timing, severity beyond the serious classification, causal assessment, or participant-level overlap. The serious-event counts should not be confused with the broader adverse-event counts: the record separately lists 52 participants with other adverse events in the OT329 Solis group, 47 in the Advair Diskus group, and 7 in the placebo group.

These counts do not establish comparative safety by themselves. Interpretation depends on the definitions, follow-up period, exposure, and analysis population, and those details are not fully reported in the registry record. The figures are descriptive summaries rather than a substitute for a complete safety analysis.

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

The registry record reports an equivalence analysis of OT329 Solis and Advair Diskus for the Day 1 FEV1 area-under-the-curve endpoint. The sponsor’s ANCOVA test/reference ratio is 1.080, with a 90% confidence interval from .8 to 1.25, and the record labels the analysis as equivalence. That is the central result for the study’s stated active-treatment question. The equivalence margin and full model details are not reported in the registry record, which limits independent review of the decision rule.

The unadjusted recalculations address a separate question: how each active group’s mean compares with placebo. OT329 Solis versus placebo has a reported mean difference of 2.34 liters, with a 95% confidence interval from -0.148 to 4.828. Advair Diskus versus placebo has a reported mean difference of 2.881 liters, with a 95% confidence interval from 0.392 to 5.37. These figures should not be treated as a reproduction of the sponsor’s active-treatment comparison.

The results concern a specific endpoint measured over 0 to 12 hours after dosing on Day 1. They do not establish what happened outside that measurement window or on other outcomes. The registry lists adverse-event counts, but those counts do not by themselves provide a complete comparative safety assessment. In general, endpoint results are most informative when considered with their population, measurement time, comparator, analysis method, and uncertainty.

The study’s record does not include the equivalence margin, detailed missing-data approach, full analysis plan, or original enrollment assumptions. Consequently, the posted result can be described, but not fully reconstructed from the registry entry. The results should not be expanded into claims about longer-term effects or clinical benefit beyond what this endpoint and analysis address. No medical advice follows from these statistical results.

17. Why This Trial Matters Statistically

This trial illustrates why the comparison named in a statistical result matters as much as the endpoint itself. The sponsor’s question was whether OT329 Solis and Advair Diskus were equivalent on a lung-function endpoint. The sponsor’s analysis reports an adjusted test/reference ratio. The unadjusted recalculations instead compare each active treatment with placebo. Those are not interchangeable contrasts, even though they use the same endpoint data.

It also illustrates why a p-value should not be read in isolation. The sponsor analysis is labeled as equivalence, a framework that depends on prespecified bounds and a decision rule. The registry record reports the ratio, interval, and p-value but does not report the equivalence margin. Without that detail, readers cannot independently reconstruct the equivalence criterion. A p-value alone does not communicate the size of the difference, its precision, or the bounds relevant to equivalence.

The confidence intervals also demonstrate the role of precision. The placebo-based recalculations include intervals that reflect uncertainty in the estimated mean differences, and the placebo group is smaller than either active group. Point estimates and p-values do not replace interval-based interpretation, particularly when the comparator group sizes differ.

Finally, the record shows why statistical interpretation depends on documentation. The ITT population is named, but missing-data handling and the full analysis plan are not reported. The registry flags a discrepancy, yet does not explain its source. Recognizing those limits allows a careful account of the posted results without treating unadjusted recalculations as the sponsor’s analysis or drawing conclusions beyond the measured endpoint.

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 primary result is limited to serial FEV1 measurements during the 0 to 12 hours after the first dose on Day 1. The registry record does not report outcomes across a longer follow-up period. The endpoint is a continuous lung-function measure, and the posted group summaries do not provide individual participant data or the distribution of outcomes.

The sponsor’s ANCOVA comparison is reported as an equivalence analysis, but the equivalence margin, model covariates, and detailed decision rule are not reported in the registry record. The record also flags a discrepancy between the sponsor analysis and the recalculated comparisons. Its specific cause is not reported. Accordingly, the recalculations should be interpreted only as unadjusted active-versus-placebo contrasts, not as a substitute for the sponsor’s test/reference result.

The registry identifies the primary endpoint population as ITT but does not explain the analysis population definition or how missing endpoint data were handled. It does not report missingness, imputation, sensitivity analyses, or the original sample-size justification. The relation between total enrollment and the endpoint group counts is also not explained. The adverse-event populations have different listed counts from the endpoint groups, with no explanation of the population definitions.

The record lists one secondary outcome and reports adverse-event counts, but the available information does not provide all details needed to assess event ascertainment, follow-up, or causal attribution. The registry does not state the complete multiplicity strategy, interim analysis plan, or treatment of protocol deviations. These omissions restrict the scope of independent statistical assessment and should not be filled by assumptions.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Clinical Efficacy Study of Salmeterol Xinafoate/Fluticasone Propionate in Asthma — NCT02260492.
• Registry record last updated 2017-06-15; status last verified 2017-03.
• Results first posted 2017-06-15.
• 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

The registry record describes a completed randomized, quadruple-masked, parallel-group Phase 1 study in patients with asthma. It lists enrollment of 879 and compares twice-daily inhaled OT329 Solis, Advair Diskus, and placebo. The primary endpoint is the area under the serial FEV1-time curve from 0 to 12 hours after dosing on Day 1.

The sponsor reports an ANCOVA test/reference ratio of 1.080, with a 90% confidence interval from .8 to 1.25, and classifies the comparison as equivalence. Separate unadjusted recalculations compare each active group with placebo. The registry flags a discrepancy, so the sponsor analysis takes precedence for its stated active-treatment question. Important details, including the equivalence margin and missing-data methods, are not reported in the registry record.