MK0476 Study in Adult Patients With Acute Asthma (0476-322): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for MK0476 Study in Adult Patients With Acute Asthma (0476-322) (NCT00229970), a randomized phase 3 study. The primary outcome is The Time-weighted Average of Change in Forced Expiratory Volume in One Second (FEV1).

2. Clinical Question

The registry describes a study of intravenous administration in adult patients with acute asthma. Its primary endpoint concerns change from the pre-allocation baseline, weighted by the interval between each measurement and the measurement immediately before it. The outcome record gives estimates for the two active groups and placebo, and reports an ANCOVA comparison of each active group with placebo.

This is a focused question about a short-term lung-function measure after study drug administration. It does not by itself address longer-term asthma outcomes, other aspects of clinical status, or whether any observed group difference is important to patients. Those questions require information beyond the posted primary endpoint.

3. Trial Design

The registry record identifies this as a randomized, double-blind, parallel-group study with a placebo comparator. The phase field lists Phase 3, while the official title describes it as a Phase II/III placebo-controlled double-blind study. The reported overall enrollment is 225. The condition is asthma, and the study status is completed.

The record gives three outcome groups: Montelukast 7 mg, Montelukast 14 mg, and placebo. It also describes the intervention arms as MK0476 7 mg injection and MK0476 14 mg injection, with placebo as the comparator. The intervention listing names montelukast sodium. These labels are reproduced as recorded; the naming variation is relevant when interpreting which intervention the outcome groups represent.

The registry lists a study start of 2005-09 and primary completion of 2006-10. It identifies Organon and Co as the sponsor. These are record details and do not establish how participants were recruited, how allocation was generated or concealed, or how the study was conducted at individual sites. Those operational details are not reported in the registry record.

Randomization is intended to make treatment groups comparable on average, while double masking is intended to limit differences in care or assessment that could arise when group assignment is known. A parallel-group design assigns participants to a group whose results are compared with the other groups. The registry identifies these design features, but does not report enough detail to assess how successfully they were implemented.

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: Patients with acute exacerbation of bronchial asthma received standard treatments of inhaled β-agonist or oxygen inhalation to treat the acute exacerbations during the 60 minutes in the screening period before the study randomization.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Last observed value during the 60 minutes treatment period was used in the Full Analysis Set (FAS)

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 The Time-weighted Average of Change in Forced Expiratory Volume in One Second (FEV1), measured over baseline over the first 60 minutes.

The primary endpoint is the time-weighted average change in forced expiratory volume in one second (FEV1), expressed in liters. FEV1 is the volume of air exhaled in the first second of a forced expiration. The registry describes the endpoint as change from the pre-allocation baseline over the first 60 minutes after study drug administration.

Weighting by the time interval between measurements gives the measurements influence according to the intervals they represent, rather than treating each reading as if it covered the same duration. This can be useful when observations are not equally spaced. The stated endpoint therefore summarizes lung-function change across a short post-administration period, rather than representing a single measurement at one time point.

The registry reports least-squares means and 95% confidence intervals for the outcome groups. The endpoint population is the Full Analysis Set, described as using the last observed value during the 60-minute treatment period. The record does not provide further detail about the timing or number of measurements, the handling of participants without an observed value, or the operational definition of the FAS.

FEV1 provides a quantitative measure of airflow, but a change in this measure is not a complete account of a person’s asthma status. The endpoint’s short time frame also limits what it can say about effects beyond the first 60 minutes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports group-level least-squares means for a continuous outcome and confidence intervals around those estimates. A continuous outcome can take values across a measurement scale; in this case the scale is liters of FEV1 change. A mean summarizes the central tendency of observed values, while a least-squares mean is an estimate from a statistical model. It may account for terms in that model, but the registry record does not describe the model used to obtain the group-level least-squares means.

What does a confidence interval convey?

A confidence interval communicates uncertainty associated with an estimate under the assumptions of the statistical method. It is not a range that contains a specified proportion of individual participant outcomes, nor does it account automatically for every source of uncertainty, such as measurement limitations or missing data. The posted group intervals give a sense of precision for each group estimate. The contrast intervals give precision for the reported comparisons with placebo.

The 95% confidence intervals for the group estimates are 0.04 to 0.15 liters for Montelukast 7 mg, 0.12 to 0.23 liters for Montelukast 14 mg, and -0.05 to 0.06 liters for placebo. For the ANCOVA comparisons, the intervals are 0.01 to 0.16 liters for Montelukast 7 mg versus placebo and 0.09 to 0.24 liters for Montelukast 14 mg versus placebo. The intervals apply to the estimates named in the record; they should not be interchanged between group estimates and contrasts.

What does ANCOVA contribute?

ANCOVA, or analysis of covariance, compares groups while accounting for one or more covariates included in the model. In general, this can improve precision or address chance imbalance in measured covariates. The registry labels the reported comparisons as ANCOVA and describes the contrast parameter as Mean Difference (Final Values). It does not report which covariates were included, the model specification, or the assumptions checked. It is therefore not possible to assess those details from the record.

The two reported ANCOVA contrasts are Montelukast 7 mg versus placebo and Montelukast 14 mg versus placebo. Their estimates are 0.09 and 0.17 liters, respectively. The reported p-values are 0.022 and < 0.001. A p-value summarizes how incompatible the observed data are with a specified null model, under the analysis assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. The record does not state whether these comparisons were part of a prespecified testing sequence or how multiple comparisons were handled.

Why does time weighting matter?

The endpoint definition says that the interval between a measurement and the preceding measurement is used as the weighting factor. In general, weighting can make a set of measurements represent time intervals of different lengths more appropriately than a simple average would. The precise calculation, measurement schedule, and handling of any irregular observations are not detailed in the registry record. The reported time frame is baseline over the first 60 minutes after study drug administration.

What do the analysis populations and safety counts tell us?

The primary endpoint population is described as the FAS, with the last observed value during the 60-minute treatment period used. The record does not define the FAS further or describe whether any imputation beyond that stated approach was used. It does not report the number of participants with an observed primary outcome in each group or the amount and pattern of missing outcome data. Such details matter because analysis results can depend on which participants contribute data and how missing measurements are handled.

For safety, the registry lists serious adverse event counts of 2 for Montelukast 7 mg, 4 for Montelukast 14 mg, and 4 for placebo. Other adverse event counts are 23, 11, and 13, respectively. The at-risk denominators are not reported in the registry record, and the event counts therefore cannot be interpreted as group-specific rates from the information recorded. The record also lists serious adverse event terms and percentages, including Asthma at 5.6%, Abdominal pain at 1.3%, Acute tonsillitis at 1.3%, and Gastritis at 1.3%.

The separate planning illustration is based on the observed effect under stated assumptions, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such calculations concern planning for a future study under those assumptions. They are not observed power, do not describe the power achieved by this completed trial, and do not replace the trial’s reported analysis. The record does not report the trial’s own sample-size justification or statistical analysis plan.

10. Analyses Reported by the Sponsor

The inferential results recorded for the active-versus-placebo comparisons are the sponsor’s ANCOVA analyses. For Montelukast 7 mg versus placebo, the reported mean difference in final values is 0.09 liters, with a 95% confidence interval of 0.01 to 0.16 and p = 0.022. For Montelukast 14 mg versus placebo, the corresponding estimate is 0.17 liters, with a 95% confidence interval of 0.09 to 0.24 and p < 0.001.

The registry also presents least-squares mean estimates and confidence intervals for each group. Those group summaries are not a substitute for the sponsor’s ANCOVA contrasts: a direct comparison can depend on the model and covariates, which are not described in detail in the record. The reported ANCOVA parameter is labelled Mean Difference (Final Values), while the primary endpoint is described as a time-weighted average change from baseline. The record does not explain this terminology difference.

No discrepancy is flagged in the registry analysis record. The reported sponsor analyses should therefore be read as the direct inferential results available in the record, without treating the separate group summaries as an independent adjusted comparison. Details sufficient to reproduce the ANCOVA estimates are not reported in the registry record.

11. Multiplicity, Missing Data and Analysis Populations

The registry reports two primary-outcome comparisons with placebo: Montelukast 7 mg and Montelukast 14 mg. It does not report whether the comparisons were tested under a prespecified hierarchy, whether any multiplicity adjustment was applied, or how the type I error rate was managed across the analyses. Without that information, the p-values should be read as the values reported for the individual ANCOVA analyses rather than as evidence that a particular multiplicity strategy was used.

No secondary outcome measures are posted in the record. This does not establish that no secondary outcomes were collected; it means they are not reported in the registry results. The record lists one outcome measure and two analyses.

The primary population is identified as the Full Analysis Set, and the outcome description says the last observed value during the 60-minute treatment period was used. The registry does not state the FAS inclusion rules, provide group-specific counts contributing to the endpoint, or describe missingness by group. It also does not clarify whether other missing-data methods were used. The last-observed-value statement alone is not enough to infer the full missing-data procedure or its assumptions.

Missing data can affect interpretation if the chance of a measurement being absent is related to participants’ outcomes or group assignment. General statistical practice examines the amount, pattern, and reasons for missingness and considers whether the analysis method is appropriate. Those details are not reported in the registry record, so the effect of missing data on these estimates cannot be assessed from the posted information.

The registry also does not report an interim-analysis plan, stopping rules, or the trial’s statistical analysis plan. Their absence from the record should not be taken as evidence that such procedures were or were not used.

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

The posted results describe a short-term continuous lung-function outcome in a randomized, double-blind, placebo-controlled study of adults with acute asthma. The group-level estimates are positive for the two active groups and close to zero for placebo. The sponsor’s reported ANCOVA contrasts are positive, with 95% confidence intervals from 0.01 to 0.16 liters for Montelukast 7 mg versus placebo and from 0.09 to 0.24 liters for Montelukast 14 mg versus placebo.

These are estimates of group-level differences for the recorded outcome and analysis. They do not describe the experience of every participant, and the confidence intervals do not show the full spread of individual responses. The record does not provide a threshold for judging whether a difference is clinically meaningful. Statistical evidence and clinical importance are distinct: a result can be estimated with some precision without establishing how consequential it is for patients.

The endpoint covers baseline through the first 60 minutes after study drug administration. It therefore does not answer questions about longer-term lung function, symptoms, exacerbations, other health outcomes, or durability. No secondary outcomes are posted in the record. The reported estimates also do not establish that the same findings would apply in other populations or settings.

The registry’s description of the primary endpoint as a time-weighted average change from baseline differs in wording from the ANCOVA parameter label, Mean Difference (Final Values). The record does not explain the relationship between those quantities. This limits how specifically the reported contrasts can be linked to the endpoint definition.

Finally, the record does not provide the covariates or full model specification for ANCOVA, missing-data details, or a multiplicity strategy. Those omissions constrain independent assessment of precision and robustness. The results should be understood as the registry’s reported short-term analyses, not as a complete account of efficacy, safety, or the trial’s full statistical conduct.

13. Why This Trial Matters Statistically

This study is statistically informative because it reports a continuous physiological endpoint in a randomized, double-blind, placebo-controlled design and gives both group estimates and active-versus-placebo analyses. Considering both kinds of estimates helps distinguish the value reported for each group from the modeled contrast used for inference. Confidence intervals also make the precision of the estimates visible rather than presenting point estimates alone.

The endpoint’s time-weighted definition is another important feature. When measurements represent unequal time intervals, weighting by the interval can provide a summary that reflects those intervals. The approach is meaningful only when the measurement schedule, weighting procedure, and treatment of incomplete observations are sufficiently clear. The registry gives the broad definition and time frame, but not all calculation details.

The record also illustrates why naming and estimand consistency matter. The intervention descriptions refer to MK0476 injections, the intervention listing names montelukast sodium, and the outcome groups are labelled Montelukast. In addition, the primary endpoint is framed as a time-weighted change from baseline, while the ANCOVA contrasts are labelled as differences in final values. Clear links between intervention identity, endpoint definition, and model parameter are needed for readers to understand exactly what was estimated.

Finally, the posted results show why p-values should not carry the entire interpretation. The estimates, intervals, analysis population, endpoint time frame, and undocumented model details all contribute to judging what the data say. The registry gives useful numerical results, while leaving several design and analysis details unreported.

14. 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.

Several trial-specific reporting gaps limit interpretation. The record uses varying intervention labels: the intervention arms are described as MK0476 injections, the intervention name is montelukast sodium, and the outcome groups are labelled Montelukast 7 mg and Montelukast 14 mg. The record does not explain the naming variation. Readers should retain the group labels as recorded rather than infer additional information about the formulation.

The primary endpoint is described as a time-weighted average change from baseline, but the reported ANCOVA parameter is labelled Mean Difference (Final Values). The record does not explain how the latter relates to the stated endpoint or provide enough methodological detail to determine whether these are equivalent summaries. The ANCOVA covariates and model specification are also not reported.

Other missing details include the randomization and allocation-concealment procedures, the operational definition of the FAS, the number of participants contributing endpoint data by group, the measurement schedule, and the extent and pattern of missing outcomes. The record does not report a multiplicity strategy, the trial’s sample-size justification, or its statistical analysis plan. These omissions prevent a full assessment of robustness and prespecification.

Safety reporting is limited by absent at-risk denominators. The registry lists adverse event counts, but without those denominators the counts cannot be interpreted as comparable rates across groups. The record also does not provide enough detail to assess the completeness of adverse-event reporting from the posted figures alone.

Lastly, the primary endpoint is restricted to the first 60 minutes after study drug administration. The record contains no posted secondary outcome results, so the primary endpoint cannot speak to broader or longer-term outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: MK0476 Study in Adult Patients With Acute Asthma (0476-322) — NCT00229970.
• Registry record last updated 2022-02-02; status last verified 2022-01.
• Results first posted 2009-07-17.
• 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.

18. Record Summary

The registry describes a completed randomized, double-blind, parallel-group, placebo-controlled Phase 3 study in adults with acute asthma. The official title calls it a Phase II/III study. Enrollment is recorded as 225, with a start of 2005-09 and primary completion of 2006-10. Organon and Co is listed as sponsor.

The primary outcome is the time-weighted average change in FEV1 from baseline over the first 60 minutes, reported for the FAS. The registry gives least-squares mean estimates and 95% confidence intervals for Montelukast 7 mg, Montelukast 14 mg, and placebo, along with two ANCOVA comparisons against placebo. The outcome group labels and intervention descriptions vary in naming, and the relationship between the endpoint definition and ANCOVA parameter label is not explained.

The registry reports no secondary outcome measures. It does not report key details of the statistical model, missing-data handling, multiplicity procedures, or the trial’s own sample-size justification. These limits matter when interpreting the reported estimates and p-values.