The Safety and Effectiveness of MK0476 (Montelukast) in Patients With Chronic Asthma (0476-388): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Safety and Effectiveness of MK0476 (Montelukast) in Patients With Chronic Asthma (0476-388) (NCT00739297), a randomized phase 1 study. The primary outcome is Change From Baseline in FEV1 Over 4 Hours.

2. Clinical Question

3. Trial Design

NCT00739297 is recorded as a completed Phase Ib study sponsored by Organon and Co. It enrolled 68 patients with chronic asthma and compared montelukast with placebo. The registry classifies the design as randomized, double-masked and crossover. These design features indicate that treatment assignment was randomized, masking was used, and the design included more than one treatment period. The registry record does not describe the specific randomization method, masking procedures, treatment order, washout intervals or the schedule for each intervention visit.

The intervention list identifies montelukast and placebo. The reported outcome results include placebo and five montelukast dose groups: 25 mcg, 100 mcg, 250 mcg, 500 mcg and 1000 mcg. The registry's brief description says the study tested a range of doses against placebo for safety and effectiveness on improved lung function. The exact dose-period sequence and the number of treatment periods per participant are not reported in the registry record.

The primary outcome was change from baseline in FEV1 over 4 hours. Measurements were taken at baseline and at 10, 20, 30, 45, 60, 120, 180 and 240 minutes. The analysis used a time-weighted average, with the interval between consecutive measurements as the weighting factor, and standardized the result by dividing by the time associated with the last measurement. The registry also lists one secondary outcome: change from baseline in FEV1 over 90 minutes after albuterol/placebo administration.

The primary analysis population was a defined full analysis set rather than simply everyone enrolled. Participants had to be randomized, take at least one post-randomization dose at either intervention visit, and have an analyzable measurement in at least one treatment period. The result counts differ across dose groups, as expected in a crossover report where available measurements and treatment-period participation can vary. The reasons for those differing counts are 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.

Before assignment: 117 participants were screened; 49 were excluded. Randomized patients met the following criteria during the prestudy period: FEV1 (Forced expiratory volume in one second) 50-85% predicted while withholding short-acting beta agonist (SABA) and reversibility of airway obstruction \>12% following SABA at Visits 1 and 2.

Only the first 6 of 7 groups are shown.

First Intervention (Visit 3 to Visit 4)

First Washout Period of 4-7 Days

Reasons for not completing this period:

Second Intervention (Visit 5 to Visit 6)

Second Washout Period of 4-7 Days

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) population which included all randomized patients who took at least one dose of post randomization study drug (Montelukast or placebo) at either of the intervention visits and had a measurement for analysis available in at least one treatment period of the cross-over design.

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 Change From Baseline in FEV1 Over 4 Hours, measured over 0 (=baseline) to 4 hours after treatment with montelukast.

FEV1 is a measure of lung function: the volume of air forcibly exhaled in the first second of a breathing maneuver. As a general clinical concept, it is used to quantify airflow and can be measured repeatedly over a short period. This trial's primary endpoint was not a single FEV1 reading. It was the average change from baseline across measurements taken from baseline through 4 hours after treatment.

The endpoint description says the measurements at 0, 10, 20, 30, 45, 60, 120, 180 and 240 minutes contributed to the average. Each interval between consecutive measurements served as a weighting factor, so the calculation accounted for the unequal spacing of measurement times. The resulting time-weighted average was standardized by dividing by the time associated with the final measurement. The endpoint is reported in L (Liter), and the treatment-group results are least-squares means with 95% confidence intervals.

Repeated measurement can describe the time course of a short-term response more fully than reliance on one measurement alone. A time-weighted average gives a single summary of the change over the defined observation window, while retaining information from the scheduled readings. It does not describe outcomes beyond that window. The registry record does not report a clinically important threshold for interpreting a change of a particular size, nor does it report how the endpoint relates to symptoms or longer-term asthma outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measure, and the registry reports it as a least-squares mean with a 95% confidence interval. A least-squares mean is a model-based estimate of a group mean. It is often used when an analysis accounts for features of the design or data structure; the registry record does not identify the model terms or the exact estimation method used in this trial. The estimates should therefore be read as the posted model-based summaries, rather than as raw arithmetic averages.

What does the time-weighted endpoint summarize?

The primary outcome combines repeated FEV1 measurements from baseline through 4 hours. Because measurements were not equally spaced, the interval between successive readings was used to weight the changes. This creates one standardized summary across the observation window rather than treating every recorded time point as equally spaced. The endpoint description states that the time-weighted average was standardized by dividing by the time associated with the last measurement. The specific implementation details beyond that description are not reported in the registry record.

Repeated measurements can be correlated: readings from the same participant are not necessarily independent observations. A crossover design also means that a participant can contribute information under different treatment periods. These are general statistical considerations for repeated-measures and crossover data. The registry record does not report the model specification, the assumptions about within-participant correlation, or how period and sequence effects were handled. Those missing details limit independent assessment of the analysis.

How should the confidence intervals be read?

A confidence interval gives a range of estimates compatible with the data under the statistical method and its assumptions. A narrower interval indicates greater precision than a wider interval, although precision does not determine clinical importance. For the reported treatment differences, intervals that extend across zero include no difference as one value compatible with the interval; intervals entirely above zero do not include zero. This is a description of interval placement, not a substitute for a complete analysis plan. No p-values are reported for the dose-versus-placebo comparisons, and the registry does not state a decision threshold for interpreting them.

The group confidence intervals and the confidence intervals for differences answer different questions. The group intervals quantify uncertainty around the estimated change within each treatment group. The difference intervals quantify uncertainty around the estimated contrast between a montelukast dose and placebo. The latter are the more direct quantities for the stated dose-versus-placebo comparisons. They should not be reconstructed by comparing the endpoints of the separate group intervals, because the crossover analysis and covariance between estimates affect the contrast's uncertainty.

What can the analysis counts tell readers?

The registry reports different numbers of participants for the primary endpoint across treatment groups. In a crossover study, those numbers can reflect the participants with usable measurements in a treatment period, rather than distinct groups of people assigned permanently to one treatment. The full analysis set definition requires randomization, at least one dose of post-randomization study drug at either intervention visit, and a measurement available for analysis in at least one treatment period. The record does not explain the treatment-specific count differences or describe missing-data methods.

For the safety outcomes, the registry provides counts affected and numbers at risk for each listed treatment. Those are descriptive counts. They do not provide a complete account of event timing, severity, relation to treatment, or exposure duration. The registry does not report death counts in the displayed safety data.

What do planning illustrations mean?

Sample-size planning illustrations use the observed effect as a reference and consider detecting a stated fraction of that effect. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. Such calculations are planning illustrations, not evidence about the trial's original design, and they are not observed power. They do not show the probability that this completed trial would detect a true effect. The protocol's own sample-size justification is not reported in the registry record. The crossover structure also means that a two-arm equal-allocation illustration should not be mistaken for a description of how participants actually contributed data to the trial.

Multiplicity is a further general statistical issue when several dose groups are compared with one control. Each additional comparison can affect the overall chance of a false-positive conclusion if tests are interpreted together. The registry reports five dose-versus-placebo estimates, but any adjustment or other approach to multiplicity is not reported in the registry record. The interpretation should therefore remain tied to the posted estimates and intervals without assuming a particular multiplicity strategy.

10. Analyses Reported by the Sponsor

The registry's reported treatment contrasts are differences in least-squares means, with 95% confidence intervals. For the 25 mcg, 100 mcg, 250 mcg, 500 mcg and 1000 mcg comparisons with placebo, the posted differences are 0.04, 0.10, 0.06, 0.05 and 0.08 L, respectively. The corresponding confidence intervals are reported with those estimates. The registry does not report p-values or identify the statistical method used to estimate the contrasts.

No separate recalculated contrast values are reported in the registry record. The sponsor's posted estimates should therefore be distinguished from any simple unadjusted recalculation based on summary statistics: the latter would not reproduce an analysis that accounts for the crossover design or model-based estimation. The registry does not identify enough model details to recreate the sponsor's analysis independently. No discrepancy is flagged between sponsor-reported and recalculated results in the record. Because there is no reported recalculation with which to make a numerical comparison, no claim about agreement at the level of individual estimates is warranted. The confidence intervals and lack of reported p-values are part of the posted analysis and should be retained when describing its precision.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five montelukast dose comparisons with placebo for the primary endpoint. When several treatment contrasts are considered, multiplicity is a general concern: interpreting multiple tests as if each were the only comparison can increase the chance of at least one false-positive finding. The registry record does not report whether the comparisons were adjusted, whether any contrast was designated as primary among the doses, or whether a hierarchical testing procedure was used. Accordingly, the posted intervals should be described as reported, without assuming they control an overall error rate across all dose comparisons.

The record identifies a full analysis set. It included randomized patients who took at least one dose of post-randomization study drug at either intervention visit and had an analysis measurement available in at least one treatment period. This definition is relevant because it is not simply a statement that every enrolled participant contributed a complete set of measurements. The registry reports 68 enrolled participants, while the treatment-specific endpoint counts vary. Reasons for missing measurements or the variation in counts are not reported in the registry record.

Methods for handling missing measurements are not reported in the registry record. It is not stated whether missing observations were excluded, imputed, or addressed through the outcome model, nor are sensitivity analyses for missing data described. In a crossover design, missingness within one treatment period may affect the available within-participant comparisons; the record does not describe how that issue was handled. Details about analysis populations for the secondary outcome are not reported.

The registry also does not report interim analyses, stopping rules, protocol deviations, or a detailed statistical analysis plan. Those details should not be inferred from the final estimates. The available information supports a description of the defined analysis population, the outcomes and the posted estimates, but not a full evaluation of multiplicity control or missing-data assumptions.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety record reports zero serious adverse events among participants at risk in each listed treatment group: placebo, 25 mcg, 100 mcg, 250 mcg, 500 mcg and 1000 mcg montelukast. The corresponding numbers at risk were 67, 41, 30, 66, 25 and 36. These are recorded event counts over the reporting period; they are not estimates of the chance of a future event and do not establish that no serious events could occur.

The record also lists other adverse events: 4 for placebo, 1 for 25 mcg, 0 for 100 mcg, 3 for 250 mcg, 3 for 500 mcg and 0 for 1000 mcg. The registry does not provide further detail in these data about event type, severity, timing or attribution. Death counts are not reported in the registry record. The crossover design and differing numbers at risk also mean these counts should not be interpreted as though each treatment group were a separate, permanently assigned parallel arm. These figures describe the safety information recorded, not a complete comparison of risk.

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

The results describe estimated short-term changes in FEV1 from baseline over 4 hours among participants included in the full analysis set. The registry reports least-squares mean changes for placebo and five montelukast doses, along with dose-versus-placebo differences and 95% confidence intervals. Some contrast intervals include zero and others lie entirely above zero. These patterns indicate different degrees of statistical precision around the reported contrasts, but the registry does not report p-values or a clinically important difference threshold.

The outcome is a time-weighted average across scheduled measurements, not a single reading and not a measure of long-term disease control. It does not by itself establish effects on symptoms, exacerbations, daily functioning or outcomes after the observation window. The registry record does not report results for those outcomes in the data summarized for this analysis. The single listed secondary outcome concerns FEV1 over 90 minutes after albuterol/placebo administration, but no numerical result for it is included in the registry record for this account.

The trial is recorded as randomized, double-masked and crossover, but the record does not provide enough detail to evaluate all design and analysis choices. Treatment sequencing, washout arrangements, the statistical model, missing-data handling and multiplicity procedures are not reported. These omissions matter when interpreting contrasts from a crossover trial and several dose comparisons. The treatment-specific sample counts also vary, and the reasons are not reported.

Zero serious adverse events were recorded for each listed treatment group, while other adverse-event counts were also reported. These observations do not establish that the treatments are free from risk; the record does not provide enough detail on event types, duration or attribution to support a broader safety conclusion. Overall, the posted data are best read as estimates of a short-term lung-function endpoint with stated uncertainty, alongside limited recorded adverse-event counts, rather than as a complete account of clinical benefit or harm.

14. Why This Trial Matters Statistically

This trial is statistically interesting because its crossover structure and dose-ranging question call for careful interpretation of both the estimates and their uncertainty. The same participant may contribute measurements under more than one treatment period, so the contrast between treatment conditions is not necessarily equivalent to comparing independent groups. The registry reports model-based least-squares means, but does not identify the model specification or explain how within-participant dependence and treatment-period features were handled. That distinction matters when readers consider how the reported confidence intervals were obtained.

The trial also reports several dose-versus-placebo comparisons. Looking across multiple doses can help describe how estimates vary, but it raises the general issue of multiplicity. With no reported adjustment or testing hierarchy, conclusions should not be based on a single contrast stripped of the broader set of comparisons. The confidence intervals are particularly useful for describing the range of estimates compatible with each contrast, while remaining limited by the analysis details absent from the record.

The primary outcome is a time-weighted summary of repeated measurements rather than one isolated value. Its construction uses unequal intervals between measurements, a feature that makes the endpoint definition important for interpretation and reproducibility. The specified observation window is short, so conclusions should remain confined to that window and outcome.

Finally, the registry's different treatment-specific sample counts, defined full analysis set and limited safety detail make transparency about analysis populations and missing observations important. The posted record permits a clear description of the estimates and their precision, but leaves questions about analytic implementation unanswered. Recognizing both what the estimates show and what the record does not explain is central to sound statistical reading.

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 record does not report the detailed protocol or statistical analysis plan. In particular, it does not describe the randomization procedure, treatment order, washout interval, period effects, sequence effects, or the model used to estimate least-squares means. These are relevant features for understanding a crossover analysis. Their absence prevents a complete independent assessment of whether the analysis appropriately reflected the design.

The primary endpoint is defined in detail as a weighted average of repeated FEV1 measurements over 4 hours, but the record does not report a threshold for clinical importance. The estimates and confidence intervals can therefore be interpreted statistically, but the registry information does not establish how large a difference would matter clinically. The observed endpoint is also limited to a short measurement window and does not answer longer-term questions.

The registry reports varying numbers of participants across the treatment-specific endpoint results. Although it defines the full analysis set, it does not explain why the counts differ or report the missing-data approach. The record does not state whether sensitivity analyses were conducted. It also does not report a multiplicity strategy for the several dose comparisons, or p-values for the primary contrasts.

Safety information is limited to counts of serious and other adverse events and numbers at risk. Event descriptions, severity, timing, relationship to study treatment and death counts are not reported in the registry record. The results therefore provide a limited view of safety rather than a detailed accounting. The registry lists one secondary outcome, but the numerical findings for that outcome are not included in the registry record for this account. These limitations restrict interpretation to the posted primary endpoint estimates and recorded event counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: The Safety and Effectiveness of MK0476 (Montelukast) in Patients With Chronic Asthma (0476-388) — NCT00739297.
• Registry record last updated 2024-05-09; status last verified 2022-02.
• Results first posted 2010-04-09.
• 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

NCT00739297 is a completed Phase Ib randomized, double-masked crossover trial of montelukast and placebo in patients with chronic asthma. The registry records an enrollment of 68. Its primary endpoint was the time-weighted change from baseline in FEV1 over 4 hours, reported as least-squares means with 95% confidence intervals. The posted dose-versus-placebo differences range across the five listed montelukast doses, and their confidence intervals vary in whether they include zero. The record also reports zero serious adverse events in each listed treatment group and counts of other adverse events. Details about the statistical model, multiplicity, missing-data handling, and several design features are not reported in the registry record. The results describe a short-term lung-function outcome and should be interpreted within that scope.