Study Comparing Budesonide Hydrofluoroalkane (HFA) vs Chlorofluorocarbon (CFC) Pressurized Metered Dose Inhalers (pMDI) in Patients With Mild to Moderate Asthma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Comparing Budesonide Hydrofluoroalkane (HFA) vs Chlorofluorocarbon (CFC) Pressurized Metered Dose Inhalers (pMDI) in Patients With Mild to Moderate Asthma (NCT00667992), a randomized phase 3 study. The primary outcome is PC 20 Methacholine (Provocative Concentration of Methacholine Causing 20 % Fall in FEV1(Forced Expiratory Volume).

2. Clinical Question

This study therefore addresses a formulation comparison in a defined asthma population, but the posted primary outcome is organized by regimen rather than as one direct estimate comparing HFA with CFC. The four estimates can describe the reported within-regimen changes relative to baseline. They do not, by themselves, establish whether the formulations differ. Interpretation of a formulation contrast would require an appropriate comparison that accounts for the crossover design and the dose regimens. That analysis is not reported in the registry record.

3. Trial Design

This was a Phase 3, randomized, open-label crossover study of budesonide HFA and budesonide CFC in patients with stable, persistent, mild to moderate asthma. The registry reports 99 enrolled participants. Randomization was used, but masking was listed as none. In a crossover design, participants receive more than one treatment condition across periods, allowing comparisons within the same participant when the analysis and data support them. The precise treatment sequence, allocation details, and any washout arrangements are not reported in the registry record.

The four listed regimens were HFA 100 mcg twice daily for 2 weeks, HFA 400 mcg twice daily for 2 weeks, CFC 100 mcg twice daily for 2 weeks, and CFC 400 mcg twice daily for 2 weeks. The primary endpoint timeframe is baseline and week 2. The full analysis set was defined as randomized patients who contributed data from at least one period, with data from both low and high dose of one inhaler. Endpoint counts were 80 for HFA 100, 79 for HFA 400, 79 for CFC 100, and 78 for CFC 400.

The study start is recorded as 2008-04, primary completion as 2009-05, and status as completed. Secondary outcomes included peak expiratory flow, FEV1, FEF 25-75, exhaled nitrogen oxide, morning, evening, and total asthma symptom scores, and morning rescue medication. The registry lists 12 outcome measures and 11 posted secondary outcomes. It reports no analyses count. The protocol details, including the planned statistical model and handling of treatment period or sequence, 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.

First Intervention 100 Mcg Twice Daily

Reasons for not completing this period:

Second Intervention 400 Mcg Twice Daily

Reasons for not completing this period:

Wash-out

Reasons for not completing this period:

Third Intervention 100 Mcg Twice Daily

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS). The FAS was defined as all randomised patients who contributed data from at least one period (ie data from both low and high dose of one inhaler).

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 PC 20 Methacholine (Provocative Concentration of Methacholine Causing 20 % Fall in FEV1(Forced Expiratory Volume), measured over Baseline and week 2.

The primary endpoint was PC 20 methacholine, the provocative concentration of methacholine causing a 20% fall in FEV1. The challenge involved inhalation from an aerosol containing doubling concentrations of methacholine over a period of 2 minutes until FEV1 had fallen by 20%. The reported measure was the ratio of the concentration at 2 weeks to the concentration at baseline.

This endpoint is used to characterize airway responsiveness to a standardized challenge. A ratio describes the follow-up concentration relative to the baseline concentration; it is not itself a direct comparison between HFA and CFC. A ratio above 1 indicates that the reported concentration at week 2 was higher than the baseline concentration for that regimen, while a ratio below 1 would indicate a lower concentration. This is a general interpretation of a ratio, not a claim about an individual participant or a treatment effect.

The registry reports geometric means and 95% confidence intervals for each regimen. A geometric mean is appropriate for summarizing ratio-scale measurements that are analyzed on a logarithmic scale. The interval conveys uncertainty around each group estimate. It does not automatically provide the uncertainty or statistical test for the difference between two regimens. The registry record does not report a direct HFA-versus-CFC contrast for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports the primary measure as a geometric mean ratio with a 95% confidence interval. The ratio compares the methacholine concentration at week 2 with the concentration at baseline. These are regimen-level summaries: each arm estimate summarizes the ratio for participants contributing data to that regimen. The registry does not report individual measurements or a model-based contrast between HFA and CFC.

What does a geometric mean summarize?

For measurements that are positive and naturally interpreted as ratios, statistical analyses commonly use logarithms. The geometric mean is obtained by averaging on the logarithmic scale and transforming back to the original scale. This approach treats reciprocal multiplicative changes symmetrically and can be more suitable than an arithmetic mean when data are skewed. This is a general statistical explanation; the detailed transformation and model used for this trial are not reported in the registry record.

The endpoint's ratio scale is central to interpretation. A ratio of 1 represents no change between the two measured time points at the level of that ratio. Estimates above 1 indicate a higher week 2 concentration than baseline, and estimates below 1 indicate a lower week 2 concentration. The posted group estimates are above 1. That description does not translate directly into a formulation effect because each arm estimate compares a regimen with its own baseline rather than comparing the two inhalers directly.

How should the confidence intervals be read?

A confidence interval expresses uncertainty around an estimated quantity under the assumptions of the statistical procedure. The registry lists 95% confidence intervals for all four geometric mean ratios. A narrower interval generally indicates greater precision for that particular estimate, while a wider interval indicates more uncertainty. The interval is not a range containing every participant's response, and it is not a probability statement about the true value after the data have been observed.

Each posted interval pertains to one regimen's ratio. To assess a difference between regimens, the relevant interval would be one for the contrast itself. Such an interval can account for the relationship between repeated measurements within participants and other design features. It cannot be reconstructed from the separate intervals alone without additional information. No direct contrast interval or test is reported in the registry record.

Why does the crossover design matter?

A crossover design can allow each participant to contribute observations under multiple treatment conditions. This can support within-participant comparisons and may reduce the influence of differences between participants. It also requires attention to period, treatment sequence, and the possibility that effects from an earlier period persist into a later one. Whether and how those features were addressed is not reported in the registry record. The definition of the full analysis set indicates that some participants contributed data from at least one period, but it does not give the treatment sequence or a complete account of period-specific observations.

The study was open-label, with masking listed as none. Knowledge of the assigned inhaler can be relevant to outcomes involving symptoms or participant-reported measures. The primary outcome is based on a methacholine challenge and FEV1, but the registry does not describe assessor masking, data handling, or other procedures that could affect measurement. It is not possible to assume protections that the record does not report.

What can be said about planning calculations?

Any sample-size calculations associated with the results are planning illustrations based on the observed effect, not the trial's original design. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. For time-to-event outcomes, the stated convention is a total number of events, while other outcomes use participants per arm. The primary endpoint is not described as a time-to-event outcome.

Such calculations illustrate how a hypothetical future study's size would depend on the assumed effect and analysis conditions. They are not the number of participants actually needed under the original protocol, and they are not observed power. The sample-size justification for this trial, the assumptions used when it was designed, and any target power are not reported in the registry record. Planning calculations based on observed results are also sensitive to the estimated effect and should not be interpreted as independent confirmation of the result.

What does the registry's analysis listing mean?

The record lists no analyses count, although it does contain primary endpoint summaries and secondary outcome listings. A zero analyses count should not be treated as evidence that no statistical work was conducted. It indicates that the registry does not enumerate analyses in that field. The statistical plan, model specification, treatment contrast, covariate adjustment, and analysis diagnostics are not reported in the registry record. Consequently, the posted group estimates can be described, but a full assessment of the inferential analysis is not possible from the registry record alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and multiple secondary outcomes, including lung-function measures, exhaled nitrogen oxide, asthma symptom scores, and rescue medication. When several outcomes or comparisons are examined, the chance of obtaining apparently notable results by chance can increase. Statistical methods for controlling or interpreting that multiplicity may include prespecifying a hierarchy or adjusting tests, but the appropriate approach depends on the study plan. The multiplicity strategy for this trial is not reported in the registry record. The record also does not explain whether secondary outcomes were confirmatory or exploratory.

For the primary endpoint, the registry provides four regimen-specific geometric mean ratios and confidence intervals. It does not report a single HFA-versus-CFC contrast, a test for the formulation comparison, or a multiplicity plan for comparisons across dose and formulation. The distinction matters: separate estimates describe the groups, whereas a contrast directly addresses a between-formulation question.

The full analysis set included randomized patients who contributed data from at least one period, with data from both low and high dose of one inhaler. Endpoint counts vary across regimens. The registry record does not report why data are unavailable for some participants or periods, whether missingness was related to observed outcomes, or what assumptions or methods were used to handle missing data. It also does not report sensitivity analyses for missing outcomes.

The record does not describe a per-protocol population or another analysis population for the primary endpoint. The protocol's planned analysis population and any deviations from that plan are not reported in the registry record. These omissions limit assessment of whether the reported estimates reflect all randomized participants as intended and how robust the results are to incomplete data.

11. 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 serious adverse event terms

Serious events with the highest arm-level rate: oral candidiasis (1.2%), lower respiratory tract infection (1.2%), respiratory tract infection viral (1.2%).

The registry lists serious adverse events by regimen group, with the number at risk and the number affected. For HFA 100, 86 were at risk and 0 were affected; for HFA 400, 81 were at risk and 1 was affected; for CFC 100, 85 were at risk and 2 were affected; and for CFC 400, 79 were at risk and 0 were affected. These are group-specific registry counts, not a comparison adjusted for exposure or the crossover structure.

The listed counts of participants affected by other adverse events are 0 for each of the four groups. The registry separately lists Oral Candidiasis, Lower Respiratory Tract Infection, and Respiratory Tract Infection Viral among the top serious-event terms, each at 1.2%. These terms and percentages should be read as reported; the record does not provide enough detail to establish their relationship to the group counts or to compare risk between formulations.

Deaths are recorded as not reported in the registry record for these groups. A count of zero affected in a category does not establish that an event is impossible or that the treatments have equivalent safety. The record does not provide event timing, exposure-adjusted rates, a statistical comparison, or enough detail to determine whether events recurred in the same participant across crossover periods. These figures describe the posted safety entries, not a complete comparative safety analysis.

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

The result establishes what the registry reports for the primary measure: four geometric mean ratios comparing methacholine concentration at week 2 with baseline, each with a 95% confidence interval. The estimates are above 1 for all four listed regimens. This supports a descriptive statement that the reported group-level concentration at week 2 was higher than baseline within each regimen. It does not, on its own, answer whether HFA and CFC differ.

The distinction between within-regimen change and between-formulation difference is important. A direct formulation comparison would use a contrast designed for the randomized crossover study and its repeated observations. The registry does not report that contrast or its uncertainty. Comparing the point estimates informally, or relying on overlap between separate confidence intervals, cannot replace the intended analysis. The posted information therefore does not establish equivalence, non-inferiority, superiority, or the absence of a meaningful difference.

The endpoint is a physiological response to methacholine challenge, defined using a 20% fall in FEV1. It is not itself a symptom score or a measure of long-term disease control. The registry also lists secondary clinical and lung-function outcomes, but the results and their inferential status are not fully described in the primary outcome record. No conclusion about the overall balance of benefits and harms follows from the primary endpoint alone.

The confidence intervals quantify uncertainty for each reported group ratio under the analysis that generated them, but the statistical model and assumptions are not reported. The differing numbers contributing to each regimen, the incomplete information about missing observations, and the absence of the direct comparison further constrain interpretation. The trial's enrollment of 99 does not mean that 99 contributed to every endpoint group.

The posted results are therefore best understood as regimen-specific summaries in a randomized, open-label crossover study. They do not justify a claim that one inhaler formulation is better or worse, nor do they support treatment advice. A complete interpretation would require the planned analysis, the direct treatment comparison, details of missing-data handling, and context from the remaining outcomes and safety results.

13. Why This Trial Matters Statistically

This trial illustrates why the design and the form of the posted estimate must match the research question. The clinical question concerns HFA compared with CFC, but the primary results are separate ratios for four dose-and-formulation regimens. Those estimates answer how the week 2 methacholine concentration compares with baseline within each regimen. They do not directly estimate the difference between formulations.

The crossover model makes the distinction especially important. Repeated measurements from the same participant can be informative, but their interpretation depends on how treatment periods and sequences are handled. Separate group summaries do not show how paired observations relate to one another. Without the model and contrast, an apparently close pair of estimates cannot establish that the formulations are alike, and an apparently different pair cannot establish that they differ.

The registry also demonstrates the role of uncertainty. The 95% confidence intervals communicate precision for the four reported ratios, not for a comparison between them. Statistical readers need to identify the quantity each interval surrounds before using it to support an inference. The record's missing details about multiplicity and incomplete data further show why a numerical result is only one part of evaluating evidence.

Finally, planning calculations based on an observed effect are not a substitute for the trial's original sample-size justification or for a treatment comparison. This distinction prevents retrospective illustrations from being mistaken for observed power or prespecified evidence. The example is useful for separating descriptive estimates, inferential contrasts, design features, and planning assumptions when interpreting registry results.

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.

The registry record does not report the direct HFA-versus-CFC primary comparison, its confidence interval, or its p-value. The four regimen-specific ratios therefore cannot establish the comparative effect that the study title and objective suggest. The statistical model, including whether and how treatment, dose, period, sequence, or participant effects were represented, is not reported in the registry record.

The record describes the study as open-label and lists no masking. It does not state whether outcome assessors or analysts were masked, or describe safeguards against measurement or reporting bias. Treatment sequences, washout arrangements, and the handling of possible carryover are also not reported. These are relevant details for interpreting a crossover study, but their absence does not establish that the procedures were inadequate.

Endpoint counts vary across the four regimens, and the full analysis set requires contribution from at least one period rather than every regimen. The reasons for incomplete data, the missing-data methods, and any sensitivity analyses are not reported in the registry record. The record also does not report the primary analysis plan or explain how the listed secondary outcomes were handled in relation to the primary endpoint.

The safety entries are counts by group, without exposure-adjusted comparisons or detail about timing and repeated events. Deaths are not reported in the registry record. The posted information is therefore insufficient for a comprehensive comparative safety assessment. These limitations concern the information available in the registry record and should not be taken as proof that the underlying study lacked additional analyses or documentation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study Comparing Budesonide Hydrofluoroalkane (HFA) vs Chlorofluorocarbon (CFC) Pressurized Metered Dose Inhalers (pMDI) in Patients With Mild to Moderate Asthma — NCT00667992.
• Registry record last updated 2012-11-07; status last verified 2012-10.
• Results first posted 2012-11-07.
• 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

NCT00667992 is a completed Phase 3, randomized, open-label crossover study sponsored by AstraZeneca. It enrolled 99 patients with mild to moderate asthma and compared budesonide HFA with budesonide CFC across 100 mcg and 400 mcg twice-daily regimens, each listed for 2 weeks.

The primary outcome was the ratio of PC 20 methacholine at week 2 to baseline, summarized as a geometric mean with a 95% confidence interval. The registry posts one estimate for each of the four regimens, with endpoint counts of 80, 79, 79, and 78. All four estimates are above 1, but the registry record does not report a direct HFA-versus-CFC contrast for the primary outcome.

The record lists secondary outcomes and serious adverse event counts. It does not report the statistical model, multiplicity approach, missing-data methods, or the details needed to assess the crossover treatment comparison. Interpretation is consequently limited to the posted regimen-specific summaries and safety entries.