Relative Bioavailability of of Olodaterol and Ketoconazole: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Relative Bioavailability of of Olodaterol and Ketoconazole (NCT01153711), a randomized phase 1 study. The primary outcome is Area Under Curve From 0 to 1 Hour at Steady State (AUC0-1,ss).

2. Clinical Question

The clinical question was whether plasma exposure to olodaterol differed when olodaterol was taken with multiple doses of ketoconazole rather than alone. The registry describes ketoconazole as a p-gp inhibitor and states that the trial was intended to investigate a possible effect on olodaterol bioavailability. This is a pharmacokinetic question about drug concentration over time, not a comparison of clinical outcomes in people receiving treatment for pulmonary disease.

The primary endpoint was the area under the plasma concentration curve from 0 to 1 hour at steady state, abbreviated AUC0-1,ss. It was measured in picogram*hours/milliliter. The reported comparison was between olodaterol alone and olodaterol plus ketoconazole. The primary endpoint timeframe was day 8 of period 1 and day 14 of period 2.

The registry lists healthy participants and chronic obstructive pulmonary disease among the conditions, while the official title describes healthy male and female volunteers. The analysis population is described as a pharmacokinetic set of evaluable treated subjects meeting the stated observation and protocol criteria. The registry record does not clarify how the conditions listing relates to the volunteer population in the official title.

The result addresses the measured exposure endpoint in this study setting. It does not by itself answer whether either regimen changes symptoms, lung function, long-term outcomes, or safety in a broader patient population. Such outcomes are not the primary question described in the registry record.

3. Trial Design

The registry identifies this as a Phase I, randomized, open-label study with a parallel model. The official title calls it an open-label, fixed-sequence study. Those descriptions do not align fully: the record labels allocation as randomized and the model as parallel, while the title uses fixed sequence. The registry record does not explain how these design descriptions fit together, so the precise sequence and allocation procedures cannot be reconstructed from the record alone.

The study compared olodaterol 10 mcg administered as a solution for oral inhalation with olodaterol plus ketoconazole 400 mg as a tablet. The official title specifies olodaterol administered with the Respimat and ketoconazole given q.d. The record lists 32 enrolled participants. It reports 24 participants in the olodaterol primary-endpoint analysis group and 31 in the olodaterol plus ketoconazole analysis group. These analysis counts do not match the overall enrollment, and the registry record does not explain the difference.

The study was completed. Its start is listed as 2010-05 and primary completion as 2010-08. The sponsor was Boehringer Ingelheim. Masking is listed as none, consistent with the open-label description; the record therefore does not describe blinded treatment assignment or blinded assessment.

The primary endpoint is described for day 8 of period 1 and day 14 of period 2. Although this points to measurements in two periods, the registry record does not give enough procedural detail to resolve the difference between its randomized, parallel classification and the fixed-sequence wording in the official title. It also does not report sequence-specific procedures, washout details, or a rationale for the study design. Those details should not be inferred from the endpoint timing alone.

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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) analysis set includes all evaluable subjects in the treated set providing at least 1 observation for at least 1 PK endpoint without important protocol violations.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Area Under Curve From 0 to 1 Hour at Steady State (AUC0-1,ss), measured over Day 8 of period 1 and day 14 of period 2.

AUC0-1,ss measures the area under the plasma concentration curve for olodaterol from dosing until one hour at steady state. In general, an area-under-the-curve measure combines concentration and time, providing a summary of drug exposure over the specified interval. AUC0-1,ss is a limited-interval measure rather than a measure of exposure across the entire dosing interval.

The registry defines the endpoint’s end time as the latest time point at which at least 2/3 of the subjects in both treatment periods have quantifiable plasma olodaterol concentrations. It describes the reported geometric mean as adjusted and the geometric coefficient of variation as intra-individual. The stated unit is picogram*hours/milliliter.

Pharmacokinetic endpoints are used to characterize exposure and to examine whether co-administration is associated with a change in measured concentrations. This endpoint is suitable for the registry’s stated bioavailability question because it summarizes early plasma exposure at steady state. It does not directly measure a clinical benefit or harm. Nor does the endpoint alone establish why any observed exposure difference occurred.

The registry lists day 8 of period 1 and day 14 of period 2 as the timeframe. It does not report the detailed concentration sampling schedule, the handling of values below quantification limits, or the exact adjustment variables used to obtain the adjusted geometric means. Those methodological details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical explanation: a geometric mean is useful when measurements are positive and variation is naturally interpreted proportionally. It is calculated on a transformed scale and returned to the original scale; unlike an arithmetic mean, it gives relatively less weight to very large values. The registry says the endpoint means are adjusted geometric means. It does not report the adjustment factors or the transformation details, so those should not be assumed.

What does the reported ratio represent?

The adjusted geometric mean ratio compares the estimated endpoint level in the olodaterol-plus-ketoconazole group with the level in the olodaterol-alone group. A ratio expresses one group relative to another, rather than as an absolute difference in picogram*hours/milliliter. The reported ratio is 168.4, with a 90% confidence interval from 155.5 to 182.4. The interval communicates the estimate’s uncertainty under the fitted analysis. It is not an interval for individual responses, and it does not mean that every participant’s measurement falls within its limits.

General statistical explanation: an interval estimate depends on the model and its assumptions, including how observations are distributed and how repeated or related measurements are handled. A narrow interval can indicate greater precision than a broad interval, but precision is not the same as clinical importance. The registry does not report enough model detail to assess all assumptions independently.

What does ANOVA contribute?

The posted analysis method is ANOVA, with an adjusted geometric mean ratio as the parameter. ANOVA is a modeling framework for comparing group means while accounting for terms included in the model. The registry record does not list those terms, the model equation, the error structure, or the transformation used. Therefore, the method label identifies the broad analysis family but does not fully specify how the reported adjustment was obtained.

General statistical explanation: in pharmacokinetic comparisons, analyses of transformed exposure measures can be used to estimate ratios after returning results to the original scale. That is a general approach, not a confirmed description of every modeling step in this trial. The record’s description of adjusted geometric means and a ratio is consistent with reporting a relative comparison, but the unreported implementation details remain unknown.

How should the confidence interval and p-value be read?

The confidence interval is reported at 90%. It ranges from 155.5 to 182.4 around the adjusted ratio estimate of 168.4. A confidence interval is a measure of uncertainty, not a probability statement about a particular fixed value after the data have been observed. The interval also does not establish that the result will reproduce exactly in another study.

The registry categorizes the analysis as non-inferiority or equivalence and reports p = 1.000. General statistical explanation: a non-inferiority test asks whether a result is not worse than a specified margin, while an equivalence test asks whether the result falls within specified limits. Their interpretation depends on the margin and the hypotheses. The registry record does not state those limits or provide the test details. The reported p-value therefore cannot be interpreted on its own as evidence of equivalence or non-inferiority. It also should not be used to erase the observed ratio estimate and its interval.

Why can variation matter?

The endpoint description identifies the geometric coefficient of variation as intra-individual. A coefficient of variation expresses variability relative to the measurement scale, and an intra-individual version concerns variation within a participant rather than variation between participants. General statistical explanation: pharmacokinetic measurements can vary within and between individuals, and distinguishing these sources of variation can matter when estimating a treatment comparison. The record reports a geometric coefficient of variation of 16.4 for each group but does not give further details about its calculation or its role in the model.

Over-dispersion is a general concern when observed variability exceeds what an assumed statistical model allows. If that occurs and is not accommodated, standard errors and confidence intervals may be misleading. The registry does not report an over-dispersion assessment, so there is no basis to state whether it was evaluated or present in this analysis.

What can be inferred about planning?

The registry record does not report a sample-size justification or the assumptions used to plan enrollment. A planning illustration based on an observed effect is not evidence that the original study was designed with a particular probability of detecting that effect. Such an illustration is a hypothetical calculation under stated assumptions, not observed power. The record’s stated planning assumptions refer to a two-sided significance level of 0.05, equal allocation, a normal approximation, and effects expressed as fractions of the observed effect; however, no planning sample-size values are included in the registry record for this explanation.

The total enrollment was 32, whereas the primary analysis groups contain 24 and 31 participants. The endpoint population is defined by evaluability, treatment, available pharmacokinetic observations, and protocol compliance. The reason the analysis counts differ from enrollment is not reported in the registry record. The record also does not describe the handling of missing endpoint observations or provide a detailed account of exclusions.

10. Analyses Reported by the Sponsor

The registry reports an ANOVA analysis with an adjusted geometric mean ratio of 168.4 and a 90% confidence interval from 155.5 to 182.4. It also reports p = 1.000 and classifies the result as a non-inferiority or equivalence analysis. These are the sponsor-reported analysis results in the registry record; the description does not include the full model specification, test margins, or detailed hypotheses.

No discrepancy is flagged between the reported analysis and a recalculated comparison. The reported ANOVA result should therefore remain the principal inferential result, rather than replacing it with an unadjusted calculation from group summaries. In general, recalculations based only on summary statistics do not reproduce adjustments or modeling choices that may be part of the original analysis. No separate recalculated estimate is stated in the registry record described for this trial.

The group-level geometric means and variability measures offer descriptive context, but they are not substitutes for the adjusted ratio and its confidence interval. Without the model terms and the non-inferiority or equivalence margin, the registry’s p-value cannot establish the formal test conclusion on its own. The interpretation should retain both the reported estimate and the limitations of the available analysis description.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint of AUC0-1,ss and six posted secondary outcomes. These include Tmax,ss, urine excretion fraction and amount over the stated interval, AUC0-8,ss, clinically relevant abnormalities across several safety assessments, and investigator assessment of tolerability. The record lists eight outcome measures and six analyses, but does not provide a complete account of how all outcomes relate to those counts.

Multiplicity arises when several outcomes or comparisons are tested. General statistical explanation: as the number of tests increases, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for the collection of tests. The registry record does not report a multiplicity adjustment, a hierarchy of endpoints, or a plan for controlling error across outcomes. It is therefore not possible to determine from the record whether the posted analyses were treated as confirmatory or exploratory, or how any multiplicity was handled.

The registry identifies the primary endpoint population as a pharmacokinetic analysis set. It includes evaluable subjects in the treated set who contributed at least one observation for at least one pharmacokinetic endpoint and had no important protocol violations. This definition provides some information about inclusion, but endpoint-specific analysis populations and the numbers excluded for each reason are not reported in the registry record.

Missing-data methods are also not described. The record does not state how missing concentration measurements, unquantifiable values, incomplete endpoint records, or protocol deviations were handled in the primary analysis. The endpoint definition gives a rule for selecting the latest time point based on quantifiable concentrations in both periods, but does not explain all missing-data procedures.

The unequal analysis counts of 24 and 31 and the overall enrollment of 32 cannot be reconciled from the posted description. They should not be treated as evidence of a particular exclusion or missing-data mechanism. The registry record does not report whether missingness was related to treatment, participant characteristics, or observed exposure.

12. 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 serious adverse event figures list 32 participants at risk in each group and zero participants with serious adverse events in each group. No serious adverse event terms are listed. The death counts are not reported in the registry record. These figures describe the registry’s serious-event reporting for the listed groups; they do not establish that no event could occur outside the recorded observation or reporting framework.

For other adverse events, the registry lists 5 affected participants among 32 at risk in the olodaterol group and 9 among 32 at risk in the olodaterol-plus-ketoconazole group. These are participant counts, not event counts, and the record does not provide a full breakdown of event types in the registry record for this account. The counts alone do not establish a causal relationship or allow a reliable comparison of risks.

Safety findings in a study of this size and duration are descriptive. The record identifies the trial as Phase I and gives start and primary completion dates of 2010-05 and 2010-08. The available serious-event figures should be read as observations recorded in this trial, not as comprehensive evidence about uncommon or longer-term events. The registry record does not report the death values or list serious-event terms.

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

The principal statistical finding is a higher adjusted geometric mean AUC0-1,ss estimate for olodaterol plus ketoconazole than for olodaterol alone. The adjusted geometric mean ratio was 168.4, and the 90% confidence interval ranged from 155.5 to 182.4. This is evidence about the measured plasma exposure endpoint under the study conditions and analysis, not a direct measure of clinical response.

The interval gives information about precision around the group comparison. It does not describe the full spread of individual participant measurements, and it cannot show how the endpoint might vary in other populations or settings. The reported p-value of 1.000 is attached to an analysis categorized as non-inferiority or equivalence, but the margin and test details are not reported. A formal conclusion about equivalence or non-inferiority cannot be reconstructed from that p-value alone.

The study record describes healthy male and female volunteers in the official title and lists healthy participants and chronic obstructive pulmonary disease among the conditions. The analysis population is a pharmacokinetic set. The relationship between these descriptions is not explained. The results should therefore not be generalized automatically to people with pulmonary disease or to other groups.

The result does not establish that a clinical outcome improved or worsened, and it does not answer questions about long-term safety. The posted primary endpoint is a pharmacokinetic measure. Although the record lists safety and tolerability outcomes, the figures are limited, and death counts are not reported in the registry record.

In general, a measured association between co-administration and exposure is distinct from a clinical recommendation. Interpretation also depends on the study design, measurement procedures, analysis population, and reporting completeness. Several of those details, including the reason for the differing analysis counts and the full statistical plan, are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically useful as an example of how a pharmacokinetic comparison can be summarized using adjusted geometric means and a ratio. The endpoint is a concentration-time measure, and the ratio expresses the comparison between olodaterol alone and olodaterol with ketoconazole in relative rather than absolute terms. The confidence interval makes the uncertainty around that ratio explicit.

It also illustrates why a p-value should not be interpreted without its testing framework. The registry labels the analysis as non-inferiority or equivalence and reports p = 1.000, but does not give the margin or detailed hypotheses. Those omitted elements are central to interpreting such a test. The effect estimate and confidence interval remain important, while the formal test conclusion cannot be determined fully from the registry description.

The record further shows why analysis populations and denominators matter. Enrollment is 32, while the primary endpoint groups list 24 and 31 participants. The analysis population definition offers a general inclusion rule, but does not explain the counts. A reader cannot safely infer the reasons for the differences or the likely impact of exclusions.

Finally, the trial demonstrates limits of registry summaries. The design labels differ between the record’s randomized, parallel classification and the fixed-sequence wording in the official title. Details of the sequence, missing-data handling, multiplicity, and model specification are not reported. Recognizing these gaps is part of sound statistical interpretation: the posted estimate can be described precisely without claiming more than the record supports.

15. 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’s design descriptions are not fully consistent. It identifies randomized allocation and a parallel model, while the official title describes a fixed-sequence study. The record does not explain the relationship between these labels or provide enough detail to reconstruct the sequence of treatment administration. This limits interpretation of the design and of how period effects may have been addressed.

The overall enrollment is 32, while the primary analysis groups contain 24 and 31 participants. The analysis-set definition gives general eligibility criteria, but the registry record does not explain the counts, enumerate exclusions, or state whether endpoint-specific missing observations affected inclusion. The primary estimate therefore applies to the analyzed population as described, and the extent to which it represents all enrolled participants is unclear.

The statistical description is incomplete. ANOVA is named, but model terms, transformation details, covariance or error structure, and adjustment factors are not reported. The analysis is categorized as non-inferiority or equivalence, yet its margin and detailed hypotheses are absent. The reported p-value cannot resolve those omissions.

The registry lists multiple secondary outcomes, but does not report a multiplicity strategy or a clear endpoint hierarchy. Missing-data methods and the handling of unquantifiable concentrations are not fully described. The record also does not report the sample-size justification or provide a basis for evaluating whether the study was planned to achieve a specific level of precision.

Generalizability is limited by the Phase I pharmacokinetic focus and the population descriptions in the record. The official title refers to healthy male and female volunteers, while the conditions list also includes chronic obstructive pulmonary disease; their relationship is not clarified. The study’s primary result concerns AUC0-1,ss, not clinical outcomes. These limitations do not negate the reported estimate, but they constrain what can be concluded from it.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Relative Bioavailability of of Olodaterol and Ketoconazole — NCT01153711.
• Registry record last updated 2014-04-30; status last verified 2014-03.
• Results first posted 2014-04-30.
• 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.

19. Record Summary

The registry describes a completed Phase I study sponsored by Boehringer Ingelheim, with a start date of 2010-05 and primary completion in 2010-08. It compares olodaterol 10 mcg alone with olodaterol plus ketoconazole 400 mg. The official title describes an open-label, fixed-sequence study in healthy male and female volunteers, while the registry also lists randomized allocation and a parallel model.

The primary endpoint was AUC0-1,ss at steady state, measured in picogram*hours/milliliter. The adjusted geometric mean ratio was 168.4, with a 90% confidence interval from 155.5 to 182.4. The registry reports an ANOVA analysis classified as non-inferiority or equivalence and p = 1.000.

The record lists enrollment of 32 and primary analysis group counts of 24 and 31. It does not explain the differing counts, report the detailed statistical plan or missing-data methods, or give the non-inferiority or equivalence margin. The reported result is a pharmacokinetic comparison and does not itself establish a clinical outcome.