A Study to Look at Day to Day Changes in Lung Function in COPD Subjects Taking Albuterol/Salbutamol and Ipratropium: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Look at Day to Day Changes in Lung Function in COPD Subjects Taking Albuterol/Salbutamol and Ipratropium (NCT01691482), a randomized phase 4 study. The primary outcome is Variability in Daily FEV1, Estimated by Coefficient of Variation.

2. Clinical Question

In general, a crossover trial can compare treatment periods within participants, which may account for stable differences between people. Interpretation also depends on details such as period effects, carryover, and the analysis approach. Those protocol and analysis details are not reported in the registry record, so the design alone cannot resolve how those issues were handled.

3. Trial Design

The registry record describes a phase 4, randomized, unmasked crossover study with enrollment of 56 participants and a planned duration of 4 weeks. The listed condition is chronic obstructive pulmonary disease. The study is marked completed. Its start and primary completion dates are recorded as 2012-07-23 and 2012-10-01, respectively.

Participants were assigned to one of two sequences: albuterol/salbutamol followed one hour later by ipratropium, or ipratropium followed one hour later by albuterol/salbutamol. Each sequence is described as daily administration. The record does not give details of any washout interval, the order-generation procedure, adherence assessment, or whether sequence allocation was balanced. Those details are not reported in the registry record.

FEV1 assessments were scheduled before the first short-acting bronchodilator, approximately 1 hour after the first agent, and approximately 1 hour after the second agent. The primary outcome description characterizes daily variability from measurements collected from Day 1 to Day 10, with the outcome timeframe listed as up to 10 days. The registry record therefore describes both the treatment order and repeated lung-function measurement, but does not report the actual visit-level measurements.

Randomization is intended, in general, to reduce systematic differences in treatment assignment. Unmasked treatment means the record does not describe blinding of participants or study personnel. In crossover research, measurements from the same participant are related; appropriate analyses typically account for that within-participant relationship. The specific statistical model, treatment-period handling, and any adjustment variables are not reported in the registry record. Consequently, the design description identifies the intended comparison but is not enough to reconstruct its analysis or estimate a treatment effect.

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: This was a randomized, open-label, two-period cross-over study to evaluate the daily bronchodilator response to albuterol/salbutamol and ipratropium individually and in combination in participants with chronic obstructive pulmonary disease.

Treatment Period 1

Treatment Period 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Efficacy Population: participants in the Intent-to-Treat Population (all participants who were randomized and received at least one bronchodilator in the treatment period) who completed pre- and post- bronchodilator assessments for at least 17 visits, with no more than 3 consecutive missing days

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 Variability in Daily FEV1, Estimated by Coefficient of Variation, measured over up to 10 days.

The primary endpoint is variability in daily FEV1, estimated by the coefficient of variation. FEV1 measures the maximal volume of air a person can forcefully exhale in one second. The registry record describes spirometry before treatment and after each of the two bronchodilators, with measurements taken at study visits across the assessment period. Variability was defined as fluctuation around the mean of the daily FEV1 data collected from Day 1 to Day 10. The outcome timeframe is listed as up to 10 days.

As general statistical context, a coefficient of variation expresses the spread of measurements relative to their mean. It can help describe day-to-day inconsistency while taking the average measurement level into account. A lower or higher CV should not be interpreted in isolation as a clinical benefit or harm; interpretation depends on the comparison, measurement context, and prespecified analysis. The record also describes the half range as another variability measure, but the stated primary outcome is the CV.

The registry lists the primary outcome unit as liters. It does not report a primary endpoint estimate, uncertainty interval, or a single sequence comparison. Therefore, the measure is defined, but the magnitude and precision of the observed variability cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary measure represent?

The endpoint is a continuous measure of day-to-day FEV1 variability, summarized by the coefficient of variation (CV). The registry record describes FEV1 assessments before and after the first bronchodilator and after the second bronchodilator, and describes variability across daily observations from Day 1 to Day 10. A continuous endpoint can take a range of values rather than being limited to a yes-or-no category. The registry identifies the parameter as a mean and the dispersion as a standard error, but does not report numerical estimates for a primary sequence comparison.

As general statistical context, a mean summarizes the central level of observations. A standard error describes the precision of an estimated mean, rather than the spread of individual observations. A standard deviation instead describes the spread of observations around their mean. These quantities answer different questions and should not be treated as interchangeable. The registry record's endpoint definition also discusses half range, but that is distinct from the stated primary CV measure.

Why use a coefficient of variation?

As general statistical context, the CV relates a measure of dispersion to the mean, which can help compare relative variability when measurement levels differ. It is useful only when interpreted in light of how the underlying measurements and mean are defined. It does not directly describe the participant's average FEV1, nor does it state how many people crossed a clinical threshold. The registry record lists liters as the unit for the primary endpoint; it does not explain that unit choice or provide an estimate to interpret.

The primary outcome description also mentions half range as a variability measure. In general, a range-based statistic uses extreme observed values and can be sensitive to unusually high or low measurements. A CV uses the mean and dispersion across measurements instead. Different variability summaries can therefore convey different aspects of the data. The primary outcome is identified as CV; the record does not report a numerical comparison using either summary.

What does the crossover structure imply?

In general, crossover studies expose participants to more than one treatment condition in different sequences. Because observations within a participant tend to be related, analyses commonly account for within-person correlation rather than treating all measurements as independent. Randomization can help balance sequence assignment, but it does not eliminate the need to consider the timing and order of treatment periods.

Carryover refers generally to an effect of an earlier treatment that persists into a later period. Period effects refer to changes over time that are not caused by the treatment itself. Crossover analyses may need to address these possibilities, along with participant-level differences. The registry record names the crossover design and the two treatment orders, but does not report washout details, a crossover analysis model, or how period and carryover effects were handled. The reader therefore cannot determine from the record whether or how those considerations entered the analysis.

How should uncertainty be considered?

As general statistical context, estimates from repeated measurements are uncertain, and their precision depends on both the number of participants and the amount and quality of information from each participant. Missing measurements may reduce information or affect the composition of the analyzed population. A standard error can quantify uncertainty in an estimated mean under a specified analysis, while a confidence interval communicates a range of plausible values under its assumptions. The registry record identifies standard error as the dispersion descriptor, but does not provide a standard error or confidence interval for the primary comparison.

The record lists 16 analyses and 7 outcome measures. When several outcomes, time points, or comparisons are examined, the chance of at least one apparently notable finding can increase if multiplicity is not addressed. General methods include prespecifying a primary comparison or adjusting inference across multiple tests. The registry record does not report whether such a strategy was used. The primary outcome is not reduced to one comparison in the record, so an isolated statistical result, if encountered elsewhere, would need to be understood in the context of the full analysis plan.

What do the planning assumptions mean?

The record describes a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial was adequately powered for a particular contrast. The specific fractions and resulting participant counts are not reported in the registry record. Planning sample sizes are illustrations for future design choices and are not observed power. Observed power is not a substitute for an effect estimate and its uncertainty.

The registry record does not provide the observed primary effect needed to interpret such an illustration, nor does it give a sample-size justification from the trial's original design. The crossover structure also means that a simple two-arm planning description may not capture every aspect of the actual within-participant comparison. The record does not explain the relation between the planning illustration and the trial's design assumptions.

In short, the available methods information defines the endpoint and describes the treatment sequences, but leaves the inferential procedure and numerical findings unspecified. General statistical principles clarify what the measures and design imply; they cannot replace the missing analysis details or estimates.

10. Multiplicity, Missing Data and Analysis Populations

The record lists 7 outcome measures and 16 analyses. The primary endpoint is daily FEV1 variability, and the secondary outcomes include maximal response for the first agent, the percentage of days reaching specified FEV1 thresholds, and variability in daily inspiratory capacity measured by CV or half range. The primary outcome is not reduced to one comparison because it has several categories or time points.

As general statistical context, multiple outcomes, time points, and comparisons create a multiplicity issue: when many hypotheses are tested, some results may appear notable by chance. Researchers can address this through prespecified outcome hierarchies, adjusted significance thresholds, or other planned methods. Which approach was used, whether any outcomes were designated as key secondary outcomes, and how analyses were prioritized are not reported in the registry record. The number of analyses alone does not show that a particular adjustment was or was not appropriate.

The primary efficacy population required participants to be randomized and receive at least one bronchodilator during the treatment period, complete pre- and post-bronchodilator assessments for at least 17 visits, and have no more than 3 consecutive missing days. This is a defined subset of the intent-to-treat population. The record does not report how many participants met these criteria or how missing measurements were handled in the analysis.

In general, excluding participants or visits because of missing data can affect precision and may affect the comparability created by randomization, depending on why data are missing. Methods such as imputation or models using available repeated measurements may be considered in research, but the specific approach used in this trial is not reported in the registry record. The record also does not state whether sensitivity analyses examined alternative missing-data assumptions. Thus, the population definition is available, but the analyzed counts and missing-data strategy are not.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death (1.8%).

Among all randomized participants, 1 of 56 had at least one serious adverse event, and 16 of 56 had at least one other adverse event. These figures describe participants with events in each reporting category; they are not counts of every event if a participant experienced more than one. They also do not show which treatment period or sequence was associated with an event. The registry record lists Death as a serious adverse event term at 1.8%. It does not provide a separate death count in the group summary.

As general statistical context, adverse-event counts are descriptive safety information. A comparison of event frequencies between treatments would require appropriately reported treatment-specific exposure and event data, as well as consideration of the study design. The figures reported for all randomized participants do not establish a causal relationship between treatment and an event. They also do not, on their own, quantify relative risk or provide an uncertainty interval.

The record does not report event timing, severity details beyond the serious-event classification, treatment attribution, or participant-level overlap between serious and other events. Therefore, the 1 serious-event participant and 16 participants with other events should be read as registry counts, not as a complete account of safety by treatment sequence. No medical advice or treatment conclusion follows from these counts.

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

The study addresses a specific statistical question: how daily FEV1 variability was characterized under two sequences of albuterol/salbutamol and ipratropium in people with COPD. The registry record identifies a randomized, unmasked crossover design, describes the one-hour ordering of the agents, and defines the primary outcome as variability estimated by CV over up to 10 days. It also describes eligibility criteria for the primary efficacy population.

Those details establish what the study intended to assess, not what the comparison found. The registry record does not report the primary sequence-specific estimates, a contrast between sequences, or the uncertainty around such a contrast. It therefore cannot establish whether variability was greater in one sequence, how large a difference might have been, or how precisely any difference was estimated. The number enrolled is not a substitute for those results.

The endpoint is also narrower than a general claim about lung function. Daily FEV1 variability is not the same quantity as average FEV1, maximal response at a single visit, symptom burden, or a participant's overall clinical course. The study lists some of these other response dimensions as secondary outcomes, but does not report their results in the registry record. No conclusions about them can be drawn from the endpoint definitions alone.

As general statistical context, a crossover comparison may be informative when within-participant data are analyzed appropriately and when period or carryover effects are considered. The registry record does not report the model or related handling details. It also does not report a multiplicity strategy despite listing multiple outcomes and analyses. These omissions limit how fully the intended comparisons can be evaluated.

The appropriate reading is therefore bounded: the registry record describes the trial's question, treatment order, and measurement approach, but does not supply a numerical primary result. This does not show that the study found no difference; it means that the primary effect and its precision are not reported in the registry record. It is not a basis for asserting that either treatment sequence works or does not work.

13. Why This Trial Matters Statistically

This trial is statistically distinctive because it focuses on day-to-day variability rather than only an average measurement or a single bronchodilator response. Repeated FEV1 assessments can describe changes within participants across days and after sequential administration of two agents. That makes the definition and analysis of variability central: CV and half range summarize fluctuation in different ways, and the stated primary measure is CV.

The crossover structure also makes within-participant dependence important. In general, measurements from the same person are not independent, and treatment order may matter. Randomized sequencing offers a framework for comparing orders, but an interpretable estimate depends on the analysis accounting for repeated observations and addressing period or carryover issues where relevant. The registry record does not report those analysis details, making it a useful example of how a design label alone cannot answer every methodological question.

The record further illustrates the difference between defining an outcome and reporting its result. It specifies the primary endpoint, assessment timing, and an efficacy-population rule, but it does not give a single primary comparison estimate or its uncertainty. Without those elements, readers cannot assess effect size, precision, or the practical meaning of the contrast. Enrollment and a completed status do not resolve that gap.

Finally, multiple listed outcomes and analyses raise an interpretive question about multiplicity. This does not imply that any particular analysis was inappropriate; it highlights why a prespecified analysis hierarchy and transparent reporting are useful. The record does not state how multiplicity was addressed. Taken together, the trial matters statistically as an example of the challenges in measuring variability, analyzing crossover data, and communicating results across several outcomes.

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 most immediate limitation for interpreting this trial from the registry record is that numerical primary outcome results are not reported as one comparison. There is no sequence-specific CV estimate, between-sequence contrast, confidence interval, or p-value for a single primary comparison. The record explicitly notes that the primary outcome has several categories or time points and is not reduced to one comparison. The direction, size, and precision of the primary finding therefore cannot be assessed.

The record identifies 56 participants enrolled, but does not report how many met the efficacy-population criteria or contributed usable data to each analysis. The criteria require at least 17 completed assessment visits and no more than 3 consecutive missing days, in addition to randomization and receipt of at least one bronchodilator. The handling of missing observations, withdrawals, and incomplete treatment periods is not reported in the registry record.

Important crossover details are also absent. The registry record does not report a washout interval, the specific analysis model, or how treatment period, sequence, participant effects, or possible carryover were considered. These details matter for interpreting repeated observations and treatment-order comparisons. Masking is listed as none, but the record does not describe how that feature was considered in assessment or analysis.

The record lists multiple outcomes and analyses without describing a multiplicity strategy. It also does not provide detailed results for the secondary outcomes, nor does it state a trial-specific sample-size justification. The planning assumptions are described, but specific effect fractions and planning counts are not reported in the registry record. These limitations concern the information available in the record; they do not establish that the underlying trial lacked analyses or findings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Look at Day to Day Changes in Lung Function in COPD Subjects Taking Albuterol/Salbutamol and Ipratropium — NCT01691482.
• Registry record last updated 2018-06-20; status last verified 2018-06.
• Results first posted 2013-12-25.
• 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

This completed phase 4 study enrolled 56 participants with COPD and used a randomized, unmasked crossover design. Participants received daily albuterol/salbutamol followed by ipratropium, or the reverse order, with the second agent administered one hour after the first. The stated primary outcome was daily FEV1 variability estimated by CV over up to 10 days.

The primary efficacy population required randomized participants who received at least one bronchodilator and completed at least 17 visits, with no more than 3 consecutive missing days. The registry record lists 7 outcome measures and 16 analyses. It does not report a single primary comparison estimate, its uncertainty, the analysis model, or the missing-data and multiplicity strategies.

For safety, 1 of 56 randomized participants had a serious adverse event and 16 of 56 had another adverse event. The record lists Death as a serious adverse event term at 1.8%, without a separate death count in the group summary. The design and outcome definitions are described, but the numerical primary treatment comparison is not reported in the registry record.