Study Comparing Dual Combination of Product (Budesonide and Formoterol) Given Via Two Different Inhalers. To See Which One Results in the Best Effect on Breathing.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Comparing Dual Combination of Product (Budesonide and Formoterol) Given Via Two Different Inhalers. To See Which One Results in the Best Effect on Breathing. (NCT04078126), a randomized phase 3 study. The primary outcome is Peak Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Within 4 Hours Post-dose Following 1 Week of Treatment.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, two-period crossover pilot study with chronic dosing over 1 week. It was registered as Phase 3 and was conducted in people with severe to very severe COPD and low peak inspiratory flow. The study compared the same dual combination of budesonide and formoterol delivered through BFF MDI with a spacer or Symbicort Turbuhaler.

In a crossover design, participants receive treatments in separate periods, so treatment comparisons can use information from both periods for the same participants. The registry arm descriptions state that each treatment was followed by a washout period. The registry record does not report the washout duration, the sequence allocation details, or whether period or sequence effects were assessed. The study was open-label, so masking was not used.

Enrollment was 35. The primary endpoint results list 30 for each treatment. These values describe the posted treatment estimates; they should not be interpreted as separate parallel-group samples because the design was crossover. The primary analysis population required randomized patients to have received at least one dose and to have post-baseline spirometry data from both periods at Visits 4 and 6. The remainder of the registry's population description is truncated, so any further eligibility or exclusion rules are not reported in the registry record.

The primary completion date was 2020-12-30 and the study status is completed. Secondary outcomes included measures of FEV1, inspiratory capacity, and peak inspiratory flow at specified assessment times. The registry lists 9 outcome measures and 9 analyses, while 8 secondary outcomes are posted. Details of the randomization procedure, treatment sequence balance, and handling of period effects 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: Subjects were randomized to an open-label, 2 period crossover study comparing Budesonide Formoterol Fumarate (BFF) Metered Dose Inhalation (MDI) administered with a spacer twice daily (BID) with Symbicort Turbuhaler BID. The subjects underwent an intervening two-week washout period where they used Berodual and Budesonide MDI BID.

Period 1

Washout

Reasons for not completing this period:

Period 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified Intent-to-treat (mITT) Population included all patients who were randomized to treatment and received at least one dose of study treatment with post-baseline spirometry data from both treatment periods at Visits 4 and 6. Patients with data judged to be impacted by important protocol deviations were excluded. Patients discontinued and restarted due to the study having been put on hold for the COVID-19 pandemic used the instance of enrollment after they restarted.

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.

Population: ITT Population - all subjects who were randomized to treatment

6. Primary Endpoint

The registry lists the primary outcome as Peak Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Within 4 Hours Post-dose Following 1 Week of Treatment, measured over baseline and 4 hours post dose after 1 week of treatment.

The primary endpoint was peak change from baseline in forced expiratory volume in 1 second (FEV1) within 4 hours after dosing, following 1 week of treatment. FEV1 is the volume of air forcibly exhaled in the first second of a breathing test. The endpoint was expressed in liters and summarized as a least-squares mean.

For each visit, peak change was defined as the maximum of the FEV1 assessments within 4 hours after dosing minus baseline, provided that at least 2 non-missing values were available during that period. Thus, the endpoint captures the largest measured change in FEV1 over the specified post-dose window, rather than the average change across all measurements in that window. The registry gives the timeframe as baseline and 4 hours post dose after 1 week of treatment.

FEV1 is used in respiratory studies as an objective measure of airflow during forced exhalation. A change from baseline expresses the measurement relative to the participant's baseline value, while the post-dose window focuses on response after administration. Selecting the maximum reading emphasizes peak measured change; it does not describe the full time course of response. General statistical context: a peak endpoint may be influenced by measurement variability, and its interpretation depends on the assessment schedule and the rule for selecting the peak. Further details on the measurement schedule are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: it is a change in FEV1 measured in liters. Continuous outcomes can be summarized by a mean, which describes the central value of the observations, and an interval that conveys uncertainty around that estimate. The posted arm estimates are least-squares means. General statistical context: a least-squares mean is a model-based estimate, potentially adjusted for terms in the analysis model; the registry record does not list the model terms or explain which covariates were included.

What does the confidence interval convey?

The reported 95% confidence intervals are 0.19 to 0.322 L for BFF MDI and 0.208 to 0.34 L for Symbicort Turbuhaler. For the ANCOVA mean difference, the 95% confidence interval is -0.054 to 0.020. In general, a confidence interval gives a range of values compatible with the data and the assumptions of the statistical model, using a procedure designed to cover the true parameter at the stated rate over repeated samples. It is not a guarantee that the true value lies inside this particular interval, and it is not a range containing 95% of individual participants' measurements.

The contrast interval crosses zero. For a difference, zero represents no difference on the scale and direction used for the contrast. The interval therefore does not isolate a difference on only one side of zero. Its values indicate the uncertainty around the estimated contrast, rather than a range of participant-level responses. The registry does not report a clinically important threshold against which the interval could be judged.

How should the p-value be read?

The reported p-value is 0.345 for the ANCOVA comparison. In general, a p-value is the probability, under a specified null model and its assumptions, of obtaining a test statistic at least as incompatible with that model as the observed statistic. It is not the probability that there is no treatment difference, and it does not measure the magnitude or clinical importance of an effect. The value is above 0.05, but that does not demonstrate equality of treatments. Evidence about the range of plausible contrasts comes from the confidence interval as well as the point estimate.

Why does the crossover design matter?

In a crossover trial, each participant can receive both treatments in different periods. This design can account for stable differences between participants because treatment outcomes are observed within the same person. General statistical context: appropriate analysis may need to consider treatment, period, sequence, and within-participant correlation. The registry identifies the comparison method as ANCOVA but does not report its terms, whether these crossover features were included, or how possible carryover was handled. The record says treatment was followed by a washout period but does not give its duration.

Because of the crossover structure, the posted n of 30 for each treatment should be understood as the reported count associated with each treatment estimate, not as evidence for independent parallel groups. The mITT definition requires data from both treatment periods at Visits 4 and 6, supporting a within-participant comparison, but the registry does not fully describe the analysis population because the wording about protocol deviations is incomplete.

What does over-dispersion mean in general?

Over-dispersion occurs when observed variability exceeds what a statistical model assumes. It is especially relevant to count outcomes, where it can make standard errors too small if extra variability is ignored. The primary endpoint is continuous and the reported analysis is ANCOVA, so count-model over-dispersion is not the central issue for this result. General principles still apply: model assumptions and the match between the analysis and data affect uncertainty. The registry does not provide diagnostic checks or residual information for the primary analysis.

How should planning illustrations be understood?

Sample-size planning illustrations use the observed effect as an input and are not observed power. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set as a stated fraction of the observed effect. For time-to-event outcomes, the stated convention is the total number of events; for other outcomes, it is participants per arm. These are planning assumptions, not the original trial's design justification. The registry record does not report the trial's sample-size justification. Such illustrations do not show the probability that the completed study detected an effect, and they do not replace interpretation of the observed confidence interval.

10. Analyses Reported by the Sponsor

The registry reports the sponsor's primary comparison as an ANCOVA analysis of mean difference in final values. The estimate is -0.017, with a 95% confidence interval from -0.054 to 0.020 and p = 0.345. This is the inferential result to use when describing the trial's own analysis. The group-level least-squares means are 0.256 L for BFF MDI and 0.274 L for Symbicort Turbuhaler, but those separate estimates do not replace the ANCOVA contrast.

The record does not give the model terms, contrast-coding details, or enough information to reconstruct the adjusted comparison from the group summaries. A separate unadjusted recalculated contrast is not reported in the registry record. The discrepancy indicator is false, so no disagreement between the sponsor's result and a recalculation is flagged. The posted analysis remains the relevant comparison; the result should be interpreted using its confidence interval and the limits of the registry's methodological detail. No additional claim about adjustment or a discrepancy can be established from the record.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 9 outcome measures and 9 analyses, including the primary FEV1 endpoint and secondary measures of FEV1, inspiratory capacity, and peak inspiratory flow. Eight secondary outcomes are posted. When a study examines multiple outcomes or time points, the chance of at least one apparently positive result can increase if each is tested without adjustment. General statistical context: multiplicity procedures can control error rates across a family of tests, but the relevant family and procedure depend on the analysis plan.

Whether multiplicity was controlled for the secondary outcomes is not reported in the registry record. The registry also does not report a hierarchy of testing, a prespecified testing sequence, or whether secondary results were considered exploratory. The primary comparison should therefore be distinguished from the collection of secondary measures; the latter should not be read as if each were an independent confirmation of the primary finding.

The primary population is described as modified intent-to-treat. It included randomized patients who received at least one dose and had post-baseline spirometry data from both treatment periods at Visits 4 and 6. The registry wording then refers to data judged to be impacted by important protocol deviations, but the description ends before the rule is complete. The full population definition and its implications are not reported in the registry record.

Missing data handling is also not reported in the registry record. The endpoint definition requires at least 2 non-missing FEV1 values during the first 4 hours post dose to determine the peak at a visit. That rule describes when a peak can be calculated, but it does not explain how participants with missing observations were handled in the treatment comparison, whether any imputation was used, or how missingness differed across periods. The posted primary treatment estimates list 30 for each treatment, while overall enrollment was 35; the record does not explain the flow from enrollment to the primary analysis population.

These gaps limit assessment of selection and missing-data bias. They do not establish that such bias occurred, but they mean the registry record alone does not allow a full audit of how incomplete observations or multiple analyses affected inference.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2% reporting threshold.

Most frequent non-serious adverse event terms

The posted serious adverse event figures report 0 affected in the BFF MDI group, with 33 at risk, and 0 affected in the Symbicort Turbuhaler group, with 35 at risk. Deaths were 0 in both groups. These figures describe the registry's reported counts for the listed risk sets; they do not establish that no safety events of any kind occurred.

For other adverse events, 1 affected participant is reported among 33 at risk for BFF MDI and 1 among 35 at risk for Symbicort Turbuhaler. The registry record does not provide event terms in the listed serious-event terms field. It also does not provide enough detail to determine event timing, severity definitions for other events, relatedness assessments, or whether a participant could contribute events in both crossover periods.

General statistical context: small safety datasets can be imprecise, particularly for uncommon events. Zero reported serious events in these risk sets should not be interpreted as proof that serious events are impossible, nor should the other-event counts be used to rank the treatments. The record gives limited event counts and no comparative safety analysis. These figures are descriptive rather than a definitive test of differences in safety.

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

The primary result describes short-term, peak change from baseline in FEV1 after 1 week of treatment in a crossover pilot study. The posted least-squares means were 0.256 L for BFF MDI and 0.274 L for Symbicort Turbuhaler. The sponsor's ANCOVA estimate of the mean difference was -0.017, with a 95% confidence interval from -0.054 to 0.020 and p = 0.345. The interval includes zero, and the p-value is above 0.05.

These statistics do not establish that the inhalers are equivalent, nor do they show that any difference is clinically unimportant. Equivalence and non-inferiority require a suitable design, a prespecified margin, and an analysis that addresses that margin. Such a margin is not reported in the registry record. A non-significant result means that this analysis did not provide evidence meeting the conventional significance threshold; it does not prove the absence of a difference.

The endpoint also has a specific scope. It measures the maximum observed FEV1 change within 4 hours after dosing, conditional on at least 2 non-missing values in that period, following 1 week of treatment. It does not directly measure longer-term lung function, symptoms, exacerbations, daily functioning, or quality of life. These outcomes should not be inferred from the primary endpoint.

The randomized crossover design compares delivery methods for the same drug combination, but it was open-label and described as a pilot. The registry provides limited detail on the analysis model, missing-data handling, period effects, and the complete mITT definition. The outcome estimates therefore need to be read with that uncertainty about analytical details. The safety counts are also limited and descriptive.

In short, the record supports a description of the observed short-term endpoint estimates and their uncertainty. It does not by itself establish a clinically meaningful advantage, equivalence, long-term benefit, or a complete safety profile. No medical conclusion or treatment recommendation follows from these posted results alone.

14. Why This Trial Matters Statistically

This study illustrates why statistical interpretation should distinguish an estimate from a decision. The point estimate for the ANCOVA comparison is -0.017, but the confidence interval extends from -0.054 to 0.020. Considering the interval makes clear that the estimate is uncertain and that the data are compatible with contrasts on either side of zero. The p-value, 0.345, answers a different question and cannot establish equality.

The crossover format also matters. Participants received treatments in separate periods, with a washout period described between treatment periods. This structure can make within-participant comparisons informative, but interpretation depends on appropriate handling of period, sequence, and correlation. The registry names ANCOVA but does not report its terms or how these design features were addressed. Statistical readers should notice both what the design offers and what the record leaves unclear.

Another useful distinction is between the primary endpoint and the broader outcome set. The primary measure captures peak change in FEV1 over a defined post-dose window after 1 week. Secondary measures concern other timing or respiratory measures. Without reported multiplicity procedures, secondary findings need cautious interpretation rather than being treated as multiple independent confirmations.

Finally, the registry lists enrollment of 35 and primary outcome estimates with 30 for each treatment, alongside an mITT definition that requires measurements from both periods. The record does not fully explain the analysis population or missing-data handling. This is a reminder that a numerical result cannot be interpreted in isolation from how participants and observations entered the analysis. The study is useful for illustrating these issues, not for establishing a definitive comparative conclusion from the registry record alone.

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 leaves several trial-specific details unclear. Although the study is described as randomized and crossover, the randomization procedure, treatment sequences, and sequence balance are not reported. A washout period is described, but its duration and the rationale for its length are not reported. The record also does not explain whether period, sequence, or carryover effects were assessed.

The primary analysis is identified as ANCOVA, but the model terms, covariates, covariance structure, and contrast coding are not reported. These details would help explain how the adjusted difference relates to the least-squares means and how the crossover design was represented in the analysis. The mITT definition is truncated after mentioning patients with data judged to be impacted by important protocol deviations, so any associated exclusion rule is unclear.

The primary endpoint requires at least 2 non-missing measurements within 4 hours after dosing for a peak to be defined. The registry does not report how missing measurements or missing visits were handled, whether imputation was performed, or whether sensitivity analyses were used. Enrollment is 35, while the treatment estimates list 30 for each treatment, but the record does not provide a participant flow explanation.

The study is described as a 1-week pilot, and the registry does not report a sample-size justification or a clinically meaningful difference for the primary endpoint. The record also does not report multiplicity handling for the secondary outcomes. These omissions limit evaluation of precision, outcome selection, and the robustness of conclusions beyond the posted primary comparison. The open-label design and short treatment duration are additional features to consider when interpreting this endpoint; their specific effects on the results are not established by the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study Comparing Dual Combination of Product (Budesonide and Formoterol) Given Via Two Different Inhalers. To See Which One Results in the Best Effect on Breathing. — NCT04078126.
• Registry record last updated 2022-03-18; status last verified 2022-02.
• Results first posted 2022-03-18.
• 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

NCT04078126 was a completed, randomized, open-label, two-period crossover pilot study in subjects with severe to very severe COPD and low peak inspiratory flow. It compared budesonide and formoterol fumarate delivered by BFF MDI with a spacer against Symbicort Turbuhaler. Enrollment was 35, and the study was registered as Phase 3.

The primary endpoint was peak change from baseline in FEV1 within 4 hours after dosing following 1 week of treatment. Posted least-squares means were 0.256 L for BFF MDI and 0.274 L for Symbicort Turbuhaler. The reported ANCOVA mean difference was -0.017, with a 95% confidence interval from -0.054 to 0.020 and p = 0.345.

The result does not establish equivalence or a clinically meaningful difference. Details on model specification, missing-data handling, multiplicity, and parts of the analysis-population definition are not reported in the registry record.