This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for MethaCholine Bronchoprovocation Study (MeCIS) (NCT00705341), a randomized phase 4 study. The primary outcome is Methacholine Challenge Test Result for Phase 2.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00705341 |
| Phase | Phase 4 |
| Condition | Asthma |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Quadruple |
| Enrollment | 219 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Johns Hopkins Bloomberg School of Public Health |
| Results posted | Yes |
2. Clinical Question
Population
The study enrolled people with stable asthma and people without asthma. The registry describes participants aged 12 to 69 years and reports total enrollment of 219. Phase 1 included asthma participants and nonasthmatic controls; phase 2 compared low- and high-dose fluticasone in people with asthma.
Intervention
In phase 2, the high-dose regimen was fluticasone at 1000 mcg per day for 4 weeks. The primary endpoint assessed methacholine challenge results after medication holds.
Comparator
The phase 2 comparator was fluticasone at 250 mcg per day for 4 weeks. The broader study also planned a phase 1 comparison of methacholine challenge results between people with asthma and people without asthma.
Primary question
The primary question was whether methacholine challenge test results differed after high- versus low-dose fluticasone. The test measures airway hyperresponsiveness through PC20, the methacholine dose at which the amount of air expired in the first second during a forced expiratory maneuver is reduced by 20%. The registry says that an order-related period effect was present and that the high- and low-dose results were compared exclusively during the first period to remove that effect.
3. Trial Design
This completed phase 4 study was registered as a randomized, quadruple-masked crossover trial of methacholine bronchoprovocation in asthma. It had two distinct phases, with different questions and participant groups. The registry reports total enrollment of 219 and lists asthma as the condition under study. The study was sponsored by Johns Hopkins Bloomberg School of Public Health.
Phase 1 was intended to compare methacholine challenge results in people with asthma with results in people without asthma. The arm descriptions say that each group would perform one methacholine challenge test. Phase 2 compared low- and high-dose fluticasone in people with asthma: 250 mcg per day versus 1000 mcg per day. The primary outcome was assessed at weeks 0 and 4, and the endpoint description characterizes the value as change from baseline to 4 weeks.
The overall design is identified as crossover, but the primary outcome description also reports a significant period effect related to the order in which doses were administered. To address order, the registry says the dose comparison was limited to results during the first period. The record does not describe the sequence-generation method, the length of any washout, or how the crossover design was implemented beyond this information. Those details are not reported in the registry record.
Although the study has a randomized and masked design, the reported phase 2 endpoint comparison uses 28 participants in the high-dose arm and 23 in the low-dose arm. The registry does not explain how these analysis counts relate to the overall enrollment or to the crossover allocation. The listed start and primary completion dates are 2009-01 and 2010-02, and the study status is completed.
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.
Phase 1:Control Challenge
| Stage | Asthmatic Controls for Phase 1 | Non Asthmatic Controls for Phase 1 | Low Dose, Then High Dose Fluticasone for Phase 2 | High Dose, Then Low Dose Fluticasone for Phase 2 |
|---|---|---|---|---|
| STARTED | 126 | 93 | 0 | 0 |
| COMPLETED | 126 | 93 | 0 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 |
Phase 2: Trial
| Stage | Asthmatic Controls for Phase 1 | Non Asthmatic Controls for Phase 1 | Low Dose, Then High Dose Fluticasone for Phase 2 | High Dose, Then Low Dose Fluticasone for Phase 2 |
|---|---|---|---|---|
| STARTED | 0 | 0 | 30 | 32 |
| COMPLETED | 0 | 0 | 23 | 28 |
| NOT COMPLETED | 0 | 0 | 7 | 4 |
Reasons for not completing this period:
| Reason | Asthmatic Controls for Phase 1 | Non Asthmatic Controls for Phase 1 | Low Dose, Then High Dose Fluticasone for Phase 2 | High Dose, Then Low Dose Fluticasone for Phase 2 |
|---|---|---|---|---|
| Withdrawal by Subject | 0 | 0 | 6 | 4 |
| Did not meet post-diluent threshold | 0 | 0 | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: There was a significant period effect in the percentage change in post diluent baseline (PC20) for high- and low-dose depending upon the order in which the doses were administered. In order to remove the effect of the order, we compared the high- and low-dose MCT results exclusively during the first cross over.
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.
| Characteristic | Unit | Nonasthmatic Controls for Phase 1 | Asthmatic Controls for Phase 1 | Total |
|---|---|---|---|---|
| Participants analysed | 93 | 126 | 219 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 93 | 126 | 219 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Age Continuous | years | 33 (SD 13) | 38 (SD 15) | 35 (SD 14) |
| Sex: Female, Male: Female | Participants | 56 | 84 | 140 |
| Sex: Female, Male: Male | Participants | 37 | 42 | 79 |
| Region of Enrollment: United States | participants | 93 | 126 | 219 |
6. Primary Endpoint
The registry lists the primary outcome as Methacholine Challenge Test Result for Phase 2, measured over weeks 0, 4.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | Full Range |
| Unit | mg/ml |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the methacholine challenge test result for phase 2, reported in mg/ml as a geometric mean with a full range. The test assesses the presence and degree of airway hyperresponsiveness after a diluent baseline measurement and medication holds. PC20 is defined in the registry as the methacholine dose at which the amount of air expired in the first second during a forced expiratory maneuver is reduced by 20%. The endpoint description says the reported value represents change from baseline to 4 weeks, with assessments at weeks 0 and 4.
In general, PC20 provides a quantitative threshold for a response during a methacholine challenge rather than simply recording whether a test was performed. A geometric mean is a way to summarize measurements on a multiplicative scale; it is not the same as an arithmetic average. The full range describes the span of reported values, but it does not show how observations are distributed within that span. In this study, the registry gives geometric means of 1.19 for 4 weeks of high-dose fluticasone and 2.04 for 4 weeks of low-dose fluticasone, with full ranges of 0.1 to 26.92 and 0.16 to 48.0, respectively. These summaries alone do not provide an adjusted between-dose estimate or its uncertainty.
The test was selected to examine whether challenge results could serve as an indicator of asthma in people receiving treatment. The record also lists predictive value of the methacholine challenge test as a secondary outcome for phase 1. The numerical results for that secondary question are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted phase 2 summaries report geometric means of 1.19 mg/ml after 4 weeks of high-dose fluticasone and 2.04 mg/ml after 4 weeks of low-dose fluticasone. Their full ranges are 0.1 to 26.92 and 0.16 to 48.0, respectively. The number of participants contributing to these arm summaries is 28 for high dose and 23 for low dose. The ranges are broad, and the means are summaries rather than individual participant results. They do not by themselves describe the shape of the outcome distribution or the precision of the comparison.
The registry reports a linear regression analysis with p = 0.65 for the phase 2 comparison. It does not provide an estimated between-dose effect or confidence interval for that analysis. The p-value is therefore the only posted inferential result for this comparison. In general, a p-value describes how compatible the observed data are with a specified statistical model under a null hypothesis; it does not measure the probability that the null hypothesis is true, nor does it quantify the size of an effect. A p-value alone cannot establish that two regimens are equivalent or that any difference is clinically important or unimportant.
Interpretation also needs to account for the registry’s description of a significant period effect depending on the order in which the doses were given. The record says that, to remove the order effect, the high- and low-dose results were compared exclusively during the first period. This means that the reported approach did not use the full crossover sequence for that comparison as described in the registry. The numbers of participants in the arm summaries may therefore not represent all randomized participants or all observations collected during the study. The exact analysis population and its relationship to the crossover sequence are not reported in the registry record.
The registry provides no confidence interval endpoints for the sponsor’s comparison and no numerical estimate of its magnitude. As a result, the precision of the estimated contrast cannot be assessed from the reported inferential output. The endpoint summaries and p-value should be read together, but neither substitutes for an effect estimate with uncertainty. The phase 1 question about distinguishing people with asthma from controls is separate from the phase 2 dose comparison; the posted primary outcome summaries do not answer that phase 1 question.
These results describe the recorded measurements and analysis, not a general conclusion about treatment or asthma diagnosis. The registry’s own description of the period effect and restricted first-period comparison is an important qualification when reading the crossover design. Further details about the analysis model, adjustment variables, and handling of missing outcomes are not reported in the registry record.
9. Statistical Methods Explained
What does a crossover design contribute?
In general, a crossover design has participants receive more than one intervention over different periods, allowing comparisons that can account for stable differences between participants. The registry identifies this study as a randomized crossover trial, but it does not describe the treatment sequences, washout interval, or the specific model used to account for repeated measurements. Those design details are not reported in the registry record.
The record explicitly notes a significant period effect in percentage change in PC20, depending on the order in which high and low doses were administered. A period effect means that measurements may differ according to when they were taken, rather than only according to the treatment being compared. In general, order effects can complicate a crossover comparison because treatment, time, and sequence may be entangled. The registry says that the high- and low-dose MCT results were compared exclusively during the first period to remove the effect of order. It does not give further detail about this analysis decision or its consequences for the analysis population.
What does the reported endpoint summary convey?
The primary results are geometric means with full ranges. In general, geometric means are useful for measurements whose distribution is better represented on a multiplicative scale. A range gives the lowest and highest reported values, but it does not show the frequency of values between those extremes, the shape of the distribution, or the uncertainty around the mean. The posted summaries are 1.19 mg/ml with a full range of 0.1 to 26.92 after high-dose fluticasone, and 2.04 mg/ml with a full range of 0.16 to 48.0 after low-dose fluticasone. The registry does not report an interval around either geometric mean.
The endpoint description says the value represents change from baseline to 4 weeks, while the arm summaries are titled as 4 weeks of high- or low-dose fluticasone. The precise transformation or calculation used to form the posted geometric means is not described in the registry record. The numeric summaries should therefore be read in the terms the registry reports, without assuming additional details about how the change was calculated.
How should the p-value be read?
The reported analysis is described as linear regression, with p = 0.65 and a 95% confidence level recorded. The registry does not provide the regression coefficient or confidence interval limits. In general, a p-value evaluates the compatibility of data with a null model under the assumptions of a particular analysis. It is not an effect size and does not express the probability that a finding arose by chance. It also does not establish equivalence. A confidence interval would ordinarily convey a range of effect values compatible with the data and model, but the endpoints of the interval for this comparison are not reported in the registry record.
The analysis method is named, but the model specification is not. The record does not say which variables were included, how any within-participant correlation was handled, or whether the regression used transformed outcomes. These aspects are especially relevant to interpreting a regression analysis in a crossover study. They are not reported in the registry record, so the posted p-value cannot be independently assessed for those modeling choices.
Why can dispersion matter?
In general, over-dispersion means that observed variability is greater than a model expects. When that occurs, standard errors and inferential results from an inadequately specified model may not reflect the actual uncertainty. The registry reports full ranges that extend widely across values, but it does not report a formal dispersion assessment or identify over-dispersion as a modeling issue. The ranges alone are not enough to diagnose over-dispersion, particularly without participant-level data and model details.
The phase 2 arm counts are 28 and 23, while total enrollment is 219 across the study. These figures refer to different scopes: the total enrollment covers the study, whereas the arm counts accompany the primary endpoint summaries. The registry does not explain the full accounting of participants, including how many contributed data in each phase or why the analysis counts differ from total enrollment. It is not appropriate to treat the total enrollment as the sample size for this specific comparison.
What are the planning illustrations?
In general, sample-size planning illustrations based on an observed effect are hypothetical calculations, not measures of the power actually achieved by a completed trial. The registry record states that its planning illustrations use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. It also distinguishes calculations reported as participants per arm from time-to-event calculations reported as total events. These are planning assumptions, not a description of the trial’s original design justification. The trial’s own sample-size justification is not reported in the registry record.
The registry record does not report whether interim analyses were planned or conducted. It also does not describe a full statistical analysis plan, a multiplicity procedure, or the handling of missing outcomes. Inferences about those procedures cannot be made from the reported regression method and p-value alone.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| Regression, Linear | not reported | 0.650 |
The registry reports the sponsor’s phase 2 comparison as linear regression with p = 0.65. It records a 95% confidence level but does not report the effect estimate or the confidence interval endpoints. The posted arm summaries give geometric means of 1.19 for 4 weeks of high-dose fluticasone and 2.04 for 4 weeks of low-dose fluticasone, with full ranges of 0.1 to 26.92 and 0.16 to 48.0. These descriptive values are not the same as a regression-adjusted contrast.
A simple unadjusted re-calculation from summary statistics is not available for this endpoint: the registry indicates that values are missing or not estimable for a two-arm comparison. There is consequently no recalculated effect estimate to compare with the sponsor’s analysis. The sponsor’s own analysis takes precedence when a re-calculation cannot be made, but its reported p-value does not supply the missing effect size or interval. The underlying regression details and the reason a summary-statistic re-calculation was not estimable are not reported in the registry record.
The p-value should be interpreted as the sponsor’s reported inferential result, not as a substitute for the omitted estimate and uncertainty interval. It cannot establish equivalence between the doses or describe the size or precision of their contrast.
11. Multiplicity, Missing Data and Analysis Populations
The registry lists two outcome measures and one secondary outcome: predictive value of the methacholine challenge test for phase 1. It reports one analysis. It does not describe how many statistical tests were planned across phases, outcomes, time points, or other analyses, nor whether any adjustment for multiple comparisons was used. A multiplicity procedure is not reported in the registry record.
In general, testing several hypotheses can increase the chance of obtaining at least one small p-value even when none of the underlying effects is present. Procedures for controlling this issue depend on the set of hypotheses and the analysis plan. Without a stated plan or account of the tests conducted, the impact of multiplicity cannot be assessed. The single posted p-value of 0.65 does not resolve what procedures, if any, applied to other outcomes or analyses.
The registry describes the primary analysis as limited to first-period results because of an order-related period effect. It does not give a detailed definition of the analysis population, explain how participant exclusions were handled, or state how missing measurements were treated. No imputation method or sensitivity analysis for missing outcomes is reported in the registry record. The counts in the primary outcome summaries are 28 for high dose and 23 for low dose, but the record does not explain how those counts arose from overall enrollment of 219 or from the crossover design.
The record also does not state whether analyses followed an intention-to-treat principle, a per-protocol approach, or another population definition. It does not report interim analyses or stopping rules. These omissions limit assessment of how the reported analysis was selected and how well it represents the randomized study population. They do not establish that a particular procedure was absent; they mean that the procedure is not described in the registry record.
12. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Low Dose for phase1 | 0 | 30 | 0.0% |
| High Dose for Phase 2 | 0 | 32 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 1% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Low Dose for phase1 | 23 of 30 |
| High Dose for Phase 2 | 22 of 32 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Low Dose for phase1 | High Dose for Phase 2 |
|---|---|---|---|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | 23 of 30 | 22 of 32 |
| headache | General disorders | 22 of 30 | 22 of 32 |
| Cough | Respiratory, thoracic and mediastinal disorders | 19 of 30 | 19 of 32 |
| Rhinitis | Respiratory, thoracic and mediastinal disorders | 18 of 30 | 19 of 32 |
| Pharyngitis | General disorders | 13 of 30 | 15 of 32 |
| Hoarseness/ dysphoria | General disorders | 12 of 30 | 16 of 32 |
| Upper respiratory inflammation | Respiratory, thoracic and mediastinal disorders | 11 of 30 | 9 of 32 |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | 10 of 30 | 10 of 32 |
| Gastrointestinal discomfort and pain | Gastrointestinal disorders | 10 of 30 | 9 of 32 |
| Upper respiratory infection | Infections and infestations | 7 of 30 | 6 of 32 |
The registry reports serious adverse events for two groups: “Low Dose for phase1” and “High Dose for Phase 2.” Serious events affected 0 of 30 participants in the low-dose group and 0 of 32 in the high-dose group. The registry lists no serious adverse-event terms. Death counts are not reported in the registry record.
For other adverse events, the registry reports 23 affected participants among 30 at risk in the low-dose group and 22 among 32 at risk in the high-dose group. These figures describe participants recorded as affected; they are not counts of distinct event episodes. The record does not provide event-level details for these other adverse events in the information.
The adverse-event group labels do not exactly match the primary efficacy arm titles, and the registry does not explain whether the safety groups correspond to the same participants, periods, or analysis population as the phase 2 endpoint comparison. The safety figures should therefore be read as their own posted summaries rather than directly paired with the primary outcome counts. Zero affected by a serious adverse event in these groups describes the recorded registry counts; it is not evidence that serious events are impossible or that all safety outcomes were captured. Follow-up duration and the method of adverse-event collection are not reported in the registry record.
13. What the Result Does, and Does Not, Mean
The registry record describes an investigation of methacholine challenge testing in asthma, with a phase 1 comparison between people with asthma and nonasthmatic controls and a phase 2 comparison of low- and high-dose fluticasone. The posted primary results concern phase 2. They report geometric means of 1.19 mg/ml after 4 weeks of high-dose fluticasone and 2.04 mg/ml after 4 weeks of low-dose fluticasone. The reported p-value for the comparison is 0.65.
Those figures do not, on their own, establish whether the two regimens are equivalent, whether one is superior, or whether any observed difference matters clinically. The registry does not report an estimated between-dose contrast or confidence interval endpoints. Without those, the magnitude and precision of the comparison cannot be read from the inferential result. In general, a non-small p-value is not proof that two groups are the same; an equivalence conclusion requires an appropriate design, a prespecified margin, and analysis supporting that conclusion. Such a margin is not reported in the registry record.
The result also needs to be understood in light of the crossover design and the recorded period effect. The registry says the comparison used first-period results to remove the effect of treatment order. That decision is a stated feature of the reported analysis, but the record does not explain the complete analysis population or provide enough model detail to assess the implications fully. The arm counts accompanying the outcome summaries are 28 and 23, and their relationship to the overall enrollment of 219 is not explained.
The phase 1 purpose was to evaluate the test as an indicator of asthma in people receiving treatment, but the numerical results for its listed predictive-value outcome are not reported in the registry record. The phase 2 dose summaries therefore should not be treated as evidence about diagnostic performance. Taken together, the posted data describe a particular challenge-test outcome and a reported regression p-value, with important uncertainty about effect size, precision, analysis details, and the phase 1 results.
14. Why This Trial Matters Statistically
This trial is statistically notable because it combines two related but distinct questions: whether methacholine challenge results differ between asthma participants and nonasthmatic controls, and whether results in people with asthma differ after low- versus high-dose fluticasone. Keeping those questions separate is essential. The posted primary summaries and regression p-value address the phase 2 dose comparison; they do not supply the numerical predictive-value results listed for phase 1.
The crossover designation also makes the reported period effect important. In general, crossover studies can use within-participant comparisons, but order and period effects can complicate the interpretation of treatment contrasts. The registry says the phase 2 comparison was restricted to first-period results to address the order effect. That creates a distinction between the overall crossover design and the specific comparison reported. The record does not provide enough detail to reconstruct the analysis or determine how many randomized participants contributed to each relevant comparison.
Statistically, the example illustrates why a p-value should not be read without an effect estimate and uncertainty interval. The reported p = 0.65 is not accompanied by a regression coefficient or confidence interval endpoints. The arm summaries show geometric means and full ranges, but those descriptive summaries do not identify the adjusted contrast or its precision. A reader therefore needs to distinguish what is numerically reported from what cannot be determined.
The registry also leaves important design and analysis details undocumented, including the sample-size justification, missing-data handling, and multiplicity approach. These limitations do not negate the reported results; they define the boundary of what can be concluded from the registry record. The case underscores the value of transparent reporting of analysis populations, model specifications, effect estimates, and uncertainty alongside p-values.
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 primary outcome description reports a significant period effect and says the high- and low-dose MCT results were compared exclusively during the first period to remove the effect of order. However, the registry does not describe the crossover sequences, washout, treatment timing beyond the stated 4-week regimens, or the model used to address repeated measurements. This makes it difficult to assess how the first-period comparison relates to the randomized crossover design.
The primary outcome summaries contain geometric means and full ranges, but no interval estimates for those summaries. The sponsor’s regression analysis has a reported p-value of 0.65, but no effect estimate or confidence interval endpoints. A two-arm re-calculation from the posted summaries is not estimable. As a result, the magnitude and precision of the adjusted dose contrast cannot be assessed from the registry results.
The analysis counts of 28 and 23 are not reconciled with total enrollment of 219. The registry does not report a participant flow, a detailed analysis population, or how missing outcome measurements were handled. The method used to calculate the stated change from baseline to 4 weeks is also not described in detail.
Other trial details relevant to interpretation are not reported in the registry record, including the original sample-size justification, any interim analyses, a multiplicity plan, and the statistical model specification. The phase 1 predictive-value outcome is listed, but its numerical results are not reported. Safety summaries use group labels that differ from the primary efficacy arm titles, and the relationship between those groups and the efficacy population is not explained. These are limitations of what can be established from the registry record; they do not imply that the underlying study lacked procedures or data that were not reported.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: MethaCholine Bronchoprovocation Study (MeCIS) — NCT00705341.
- Registry record last updated 2013-02-12; status last verified 2013-02.
- Results first posted 2013-02-12.
- 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.
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19. Record Summary
NCT00705341 is a completed phase 4 randomized, quadruple-masked crossover study of methacholine bronchoprovocation in asthma. Total enrollment was 219. Phase 1 compared challenge testing in people with asthma and people without asthma; phase 2 compared 4 weeks of high-dose fluticasone at 1000 mcg per day with 4 weeks of low-dose fluticasone at 250 mcg per day.
The primary phase 2 outcome was PC20, reported as a geometric mean with a full range. The registry reports values of 1.19 for high dose and 2.04 for low dose, and a linear regression p-value of 0.65. It also notes a period effect and says the comparison was limited to first-period results. The effect estimate and confidence interval endpoints are not reported in the registry record. The listed secondary outcome is predictive value of the methacholine challenge test for phase 1, but its numerical result is not reported.