A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Inhaled Montelukast (MK-0476) in Participants With Mild or Moderate Asthma (MK-0476-380 AM3)(COMPLETED): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Inhaled Montelukast (MK-0476) in Participants With Mild or Moderate Asthma (MK-0476-380 AM3)(COMPLETED) (NCT00636207), a randomized phase 1 study. The primary outcome is Number of Participants Who Experienced At Least One Adverse Event.

2. Clinical Question

3. Trial Design

This was a phase 1 randomized, double-blind, placebo-controlled study with a parallel model. The official title describes a sequential, 3-part design that included single rising doses and rising multiple doses in healthy subjects and patients with mild or moderate asthma. The listed condition is asthma, and the study status is completed.

Montelukast inhalation powder was studied at 0.1 mg, 0.3 mg, 1 mg, 3 mg, and 10 mg, with placebo as the control. The treatment descriptions include a single-dose part followed by at least a 3-day washout. The 1 mg, 3 mg, and 10 mg groups also appear in multiple-dose parts; the descriptions state daily dosing for 5 days in Part II and, for some groups, daily dosing for 10 days in Part III. The listed descriptions for some later-part schedules are incomplete, so their full details are not reported in the registry record.

The primary safety population was defined as all participants who received at least one dose. Follow-up for the primary outcome was up to 14 days after the last dose of study drug. Registry enrollment is listed as 46. The posted safety results give group-specific counts, including 7 in each of the 0.1 mg and 0.3 mg groups, 12 in the 1 mg group, 18 in the 3 mg group, 19 in the 10 mg group, and 18 with placebo. The relationship between the registry enrollment figure and these arm-level safety counts is not explained 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.

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population: All participants who received at least one dose of study drug

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 Number of Participants Who Experienced At Least One Adverse Event, measured over Up to 14 days after last dose of study drug.

The primary endpoint is the number of participants who experienced at least one adverse event during follow-up up to 14 days after the last dose of study drug. The safety population consists of participants who received at least one dose. This endpoint counts people with one or more events, not the total number of events; a participant with multiple events still contributes once to this count.

Counting participants with any adverse event is a straightforward way to describe how often an event was reported in each treatment group. Comparing those counts with the placebo group can show the observed difference in the proportion of participants who had at least one event. It does not describe the event types, severity, duration, or number of events per participant. Those details require separate results.

The registry also reports serious adverse event counts separately. Serious events are not interchangeable with the broader primary endpoint: the primary endpoint includes any adverse event, while the serious-event summary concerns a narrower category. The primary endpoint is a safety measure, not an efficacy measure. A pharmacokinetic outcome is part of the study’s stated purpose, but a pharmacokinetic result is not reported in the registry record.

7. Results Posted in the Registry

• Montelukast 1 mg: 50.0% (6/12) versus 33.3% (6/18) on control; risk difference 16.7 percentage points (95% CI -19.0 to 52.4), risk ratio 1.50 (0.63–3.56); unadjusted two-proportion z-test p = 0.361.
• Montelukast 3 mg: 50.0% (9/18) versus 33.3% (6/18) on control; risk difference 16.7 percentage points (95% CI -15.1 to 48.4), risk ratio 1.50 (0.67–3.34); unadjusted two-proportion z-test p = 0.310.
• Montelukast 10 mg: 26.3% (5/19) versus 33.3% (6/18) on control; risk difference -7.0 percentage points (95% CI -36.5 to 22.4), risk ratio 0.79 (0.29–2.14); unadjusted two-proportion z-test p = 0.641.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is binary at the participant level: each person either experienced at least one adverse event during the stated follow-up or did not. The group counts and denominators describe the observed data. A risk difference compares the proportions with an event in two groups by subtracting one group’s proportion from the other. A positive difference indicates a larger observed proportion in the montelukast group; a negative difference indicates a smaller observed proportion. This direction describes the sample estimate, not certainty about the underlying difference.

For the 1 mg comparison, the reported risk difference is positive, with a confidence interval from -0.190 to 0.524; the unadjusted p-value is 0.361. For 3 mg, the reported risk difference is also positive, with a confidence interval from -0.151 to 0.484; the unadjusted p-value is 0.31. For 10 mg, the estimated difference is negative, with a confidence interval from -0.364 to 0.224; the unadjusted p-value is 0.641. Each interval crosses zero, the value corresponding to no risk difference. These intervals therefore include both a possible lower event proportion and a possible higher event proportion in the montelukast group.

General: a confidence interval describes a range of values compatible with the observed data under the method used. It is not a guarantee that the true effect lies in the interval, and it does not give the probability that a particular effect is true. Wider intervals indicate less precision. Small groups and a limited number of events commonly yield less precise estimates because the data contain less information about the underlying event rate.

The registry also gives relative risks and odds ratios for the selected comparisons. General: a relative risk compares event probabilities as a ratio, while an odds ratio compares event odds. Both are measures of relative association; neither should be confused with the risk difference, which is an absolute contrast. The intervals for the reported relative measures are broad. Because the risk-difference estimates and their intervals are easier to interpret in the original event scale, the discussion emphasizes them.

What does an unadjusted p-value describe?

General: a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test assumptions were true. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The three reported p-values are unadjusted. The registry record does not report whether or how the study’s original analysis plan addressed multiple comparisons. Accordingly, the p-values should be read as results for the individual comparisons, not as evidence that multiplicity was controlled.

Why are the estimates uncertain?

General: when the number of participants and events is small, moving a few outcomes between the event and no-event categories can materially change the estimated group proportions. The posted arm counts are modest, and the confidence intervals reflect substantial uncertainty. A non-significant result does not demonstrate equivalence or prove that the groups have the same event risk. Establishing equivalence would require a prespecified margin and an analysis designed for that question; these are not reported in the registry record.

The available comparison estimates are presented without adjustment. The registry record lists zero analysis records, and it does not report the original statistical analysis plan, any interim analyses, or a prespecified model for the primary endpoint. The sample-size illustrations are planning calculations based on observed effects, not evidence about the study’s original design. The registry record does not report the original sample-size justification or assumptions.

10. Confidence Intervals and Precision

Precision is limited for the posted comparisons. The risk-difference confidence intervals for 1 mg, 3 mg, and 10 mg all cross zero, so each is compatible with no difference as well as with differences in either direction. The 1 mg and 3 mg estimates favor a higher observed event proportion than placebo, while the 10 mg estimate favors a lower observed proportion; the intervals are too broad to settle those contrasts.

The group sizes underlying these comparisons are 12 participants with 1 mg and 18 with placebo, 18 with 3 mg and 18 with placebo, and 19 with 10 mg and 18 with placebo. The event counts are 6 and 6 for the 1 mg and placebo comparison, 9 and 6 for the 3 mg and placebo comparison, and 5 and 6 for the 10 mg and placebo comparison. With these limited counts, the estimates can vary meaningfully with a small change in observed outcomes.

General: a confidence interval is a measure of sampling uncertainty under the statistical method used. A broad interval signals that the data do not locate the effect precisely; it should not be read as proof of no effect. The registry does not report a prespecified equivalence or non-inferiority margin, and the intervals therefore should not be used to claim equivalence. The record also does not report a multiplicity adjustment, so the intervals and unadjusted p-values should be interpreted as individual comparisons rather than as a joint analysis across doses.

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 expressed as participants per arm, not total event counts. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. These are planning assumptions for the illustration; the trial’s own original design assumptions are not reported in the registry record.

The 80% power column gives the estimated participants per arm for a design that would have an 80% chance of detecting the chosen effect under those assumptions, if that effect were the true effect. The 90% power column gives the corresponding planning figure for a 90% chance. These are prospective design calculations, not a description of the chance that this completed trial found an effect. This is not observed power.

The rows for planning at 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect illustrate how the assumed effect size changes the required sample. For the 1 mg and 3 mg comparisons, the listed figures are the same: 137 participants per arm for 80% power and 182 for 90% power when planning for 100% of the observed effect; 240 and 320 for 75%; and 529 and 708 for 50%. For 10 mg, the corresponding figures are 666 and 892; 1,205 and 1,612; and 2,754 and 3,687.

Smaller effects require more participants to detect under the same planning framework. These figures are illustrations based on the observed estimates and should not be mistaken for the trial’s actual enrollment target or its original sample-size justification. The registry record does not report that original justification.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.333; treatment proportion p₁ = 0.500; average p̄ = 0.417.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6972 = 1.3665.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6872 = 0.5783.
4. n = (1.3665 + 0.5783)² / (0.1667)² = 136.2, rounded up to 137 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
p0 <- 0.333333333333333                          # control proportion
p1 <- 0.5                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(636207)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 137 (80% power), 182 (90% power)
 75% of observed effect: n per arm = 240 (80% power), 320 (90% power)
 50% of observed effect: n per arm = 529 (80% power), 708 (90% power)
power.prop.test: 136.2 
Simulated power at n = 137 per arm: 0.798 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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. Multiplicity, Missing Data and Analysis Populations

The registry reports three placebo comparisons for the primary adverse-event outcome: 1 mg, 3 mg, and 10 mg. The p-values are labeled unadjusted. The registry record does not report whether a multiplicity procedure was planned or used, nor does it describe a hierarchy for testing the dose comparisons. When several comparisons are made, the chance of at least one false-positive result can increase; adjustment or a prespecified testing strategy can address that concern. Without the original plan, the extent to which multiplicity was considered cannot be determined.

The registry record lists zero analysis records. It does not report the statistical analysis plan, the method used to handle missing outcome data, or whether participants were analyzed according to randomized assignment. The primary outcome population is defined as all participants who received at least one dose, a safety population. An intention-to-treat population, a per-protocol population, and their analysis rules are not reported in the registry record.

The record does not describe exclusions after randomization, treatment discontinuations, protocol deviations, or the amount and pattern of missing data. It also does not report an interim-analysis plan. These omissions make it difficult to assess how the posted participant counts were selected for analysis or whether missing observations could have affected the results.

The registry lists 12 outcome measures, but no secondary outcome result is reported in the posted results, and the number of posted secondary results is zero. The study’s stated purpose includes pharmacokinetics, but pharmacokinetic findings and their analysis methods are not reported in the registry record. The original sample-size justification and the planned statistical methods are also not reported.

14. 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 summary reports zero affected participants in each of the six listed groups: montelukast 0.1 mg, 0.3 mg, 1 mg, 3 mg, and 10 mg, and placebo. The corresponding numbers at risk are 7, 7, 12, 18, 19, and 18. No serious adverse event terms are listed in the registry record.

These figures concern serious adverse events only. They do not conflict with the primary endpoint counts, which include participants who experienced any adverse event. The posted primary counts include 2 participants in the 0.1 mg group, 4 in the 0.3 mg group, 6 in the 1 mg group, 9 in the 3 mg group, 5 in the 10 mg group, and 6 with placebo.

A zero count in these small groups means that no serious events are reported for those groups in the registry results; it does not establish that the risk is zero. Death counts are not reported in the registry record. The serious-event summary should be read as a descriptive report, not as a precise estimate of rare-event risk.

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

The results describe how many participants in each group experienced at least one adverse event during follow-up. The posted counts differ across dose groups, and the selected placebo comparisons produce estimates in different directions. Their confidence intervals cross no difference, and the unadjusted p-values are 0.361, 0.31, and 0.641. The data therefore do not precisely distinguish the underlying event risks for the compared groups.

These findings do not establish that montelukast causes more or fewer adverse events than placebo, nor do they establish that the groups have equivalent safety. A failure to show a clear difference is not proof that no difference exists. The study is an early-phase safety, tolerability, and pharmacokinetics study, and the posted primary outcome addresses adverse-event counts rather than clinical benefit.

The posted results also do not support a conclusion about efficacy, because an efficacy outcome is not reported in the registry record. Although pharmacokinetics is part of the study’s stated purpose, pharmacokinetic findings are not reported in the registry record. The serious adverse event counts are zero in each listed group, but the group sizes are limited and the record does not provide a detailed serious-event listing. These observations cannot establish the absence of rare harms.

Interpretation is further limited by the lack of reported information about the original analysis plan, missing-data handling, multiplicity, and sample-size justification. The registry enrollment figure is 46, while the posted arm-level safety counts are reported separately and their relationship is not explained. The results are best understood as descriptive findings from this study, with substantial statistical uncertainty and important details not reported in the registry record.

16. Why This Trial Matters Statistically

This study illustrates why a count of participants with an event and its uncertainty should be read together. The arm counts are easy to understand, but small groups mean that the observed differences can be imprecise. The risk-difference intervals cross zero for each posted comparison, demonstrating that the direction suggested by a point estimate is not settled by the data.

It also illustrates the distinction between statistical evidence and clinical interpretation. An unadjusted p-value does not tell a reader the probability that a treatment effect is real, and a result that does not meet a conventional threshold does not establish equality. Confidence intervals help show the range of contrasts compatible with the data, while the safety counts retain their direct descriptive meaning.

Multiple dose comparisons raise a further statistical issue. The record reports three selected comparisons with placebo and unadjusted p-values, but does not report a multiplicity plan. A reader therefore cannot determine whether the original analysis controlled the overall error rate across comparisons. The planning illustrations likewise show how assumed effect size affects design requirements, but they do not reveal the trial’s original design rationale.

Finally, the study’s stated aims include pharmacokinetics, yet those findings are not reported in the registry record. This is a reminder that a registry record can contain a primary safety result without providing every result needed to evaluate all stated aims. Careful interpretation distinguishes what the posted counts estimate from what remains unreported.

17. 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 posted outcome results are limited to the primary adverse-event counts and selected comparisons. Although the registry lists 12 outcome measures, secondary results are not reported. Pharmacokinetic findings are also not reported in the registry record despite the study’s stated pharmacokinetic purpose.

The arm sizes are modest, and the confidence intervals are broad. The comparisons are unadjusted, and the registry record does not report a multiplicity strategy or original statistical analysis plan. The handling of missing data, analysis exclusions, protocol deviations, and interim analyses is not reported. The original sample-size justification and design assumptions are likewise not reported.

The registry lists enrollment as 46, while the results give separate safety-population counts for the treatment arms. The record does not explain the relationship between the enrollment figure and those arm counts. The primary safety population is defined by receipt of at least one dose, but the record does not provide further details on randomized and analyzed populations.

The serious adverse event summary reports zero affected participants in each group, but small groups provide limited information about uncommon events. No serious-event terms are listed, and deaths are not reported in the registry record. The registry’s treatment descriptions for later multiple-dose parts are incomplete, limiting the detail available about those schedules.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Inhaled Montelukast (MK-0476) in Participants With Mild or Moderate Asthma (MK-0476-380 AM3)(COMPLETED) — NCT00636207.
• Registry record last updated 2024-05-09; status last verified 2022-02.
• Results first posted 2013-01-28.
• 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.

21. Record Summary

This completed phase 1 study was randomized, double-blind, placebo-controlled, and used a parallel model. It evaluated inhaled montelukast in dose groups of 0.1 mg, 0.3 mg, 1 mg, 3 mg, and 10 mg, with placebo as comparator. The official title describes a sequential, 3-part study involving healthy subjects and people with mild or moderate asthma.

The primary outcome was the number of participants with at least one adverse event up to 14 days after the last dose. Event counts were reported for all listed groups, with unadjusted placebo comparisons for 1 mg, 3 mg, and 10 mg. Each comparison has a confidence interval that includes no risk difference. Serious adverse event counts are zero in the listed groups.

The registry record does not report the original statistical plan, sample-size justification, missing-data methods, multiplicity approach, or pharmacokinetic results.