Inhaler Lung Deposition in Chronic Obstructive Pulmonary Disease (COPD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Inhaler Lung Deposition in Chronic Obstructive Pulmonary Disease (COPD) (NCT01721291), a randomized phase 4 study. The primary outcome is Penetration Index (LUNG DEPOSITION STUDY).

2. Clinical Question

The study also included a lung physiology component, with COPD and asthma groups receiving non-radiolabelled treatments. The listed secondary outcomes concern small-airway measures assessed with multiple-breath nitrogen washout. The registry record does not state numerical results for those outcomes. Consequently, the clinical question that can be described is the study’s measurement objective, not a conclusion about differences between treatments or changes in breathing capacity.

3. Trial Design

This completed Phase 4 study was randomized, double-masked and used a crossover model. The registry lists enrollment of 64 and identifies Imperial College London as the sponsor. The recorded start date is 2012-10-01, and primary completion is dated 2017-11-27. These are registry entries; the record does not provide further information about recruitment progress or the timing of individual participant visits.

The study had separate lung-deposition and lung-physiology groups. COPD group 1 and healthy participants received radiolabelled salbutamol treatments for lung-deposition assessment. COPD group 2 and participants with asthma received non-radiolabelled treatments in the physiology study. Across the group descriptions, the treatment regimens include aerosols of 1.5, 3.0 and 6.0 micron particle sizes, as well as a 200mcg salbutamol metered dose inhaler treatment. The aerosol treatments are described as 30mcg salbutamol, and treatment order was randomized.

The crossover design means participants were assigned treatment sequences rather than being described solely as receiving a single treatment in parallel groups. In general, crossover designs can support within-participant comparisons, because treatment responses may be compared across treatment periods for the same participant. That interpretation depends on adequate conduct of the periods and appropriate analysis. The registry record does not report the sequences, washout intervals, period lengths, or how any carryover or period effects were handled.

The primary endpoint was Penetration Index, assessed five minutes after inhalation of salbutamol. It was measured only in the lung-deposition study. The registry describes five outcome measures and names Scond and Sacin, both associated with multiple-breath nitrogen washout, as secondary outcomes. It does not report outcome estimates or analysis results. The registry status is completed, but that status alone does not establish which planned analyses were performed or reported.

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 study has four cohorts of participants, COPD1, COPD2, and Healthy volunteers, asthmatic. The study is divided into two parts: 1) The LUNG DEPOSITION and 2) the LUNG PHYSIOLOGY study. The COPD1 and Healthy volunteer cohorts take part in the Lung Deposition study. COPD 2 and Asthmatic cohorts take part in the Lung Physiology study.

Period 1

Washout

Period 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Penetration Index (PI) was only measured for the Healthy Volunteers and COPD participants from Group 1 (Lung Deposition study). The Lung PHYSIOLOGY arms, COPD2 and the asthma group, did not receive this treatment (radiolabelled salbutamol ). This is the reason that there are 0 values shown here for these groups. PI is a ratio and has no units. The PI was also not measured for the MDI as it was not possible o add a radiolabel to drug inside the MDI canister.

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 Penetration Index (LUNG DEPOSITION STUDY), measured over 5 MINUTES AFTER INHALATION OF SALBUTAMOL.

The primary endpoint is the Penetration Index (PI), a ratio intended to describe the regional distribution of inhaled salbutamol in the lungs. Lung images were acquired using gamma scintigraphy after participants inhaled salbutamol aerosols labelled with Technetium-99m. The images were divided into central and peripheral lung regions. Radioaerosol counts in those regions were used to assess how far the aerosol had penetrated into the lung.

The registry describes PI more precisely as the peripheral-to-central radioaerosol count ratio divided by the corresponding ratio from a Krypton ventilation scan. The ventilation scan provides a reference for regional lung distribution. This adjustment is intended to distinguish aerosol deposition patterns from the underlying distribution of ventilation. In general, a ratio endpoint can express a relative pattern rather than an absolute amount; its interpretation depends on the definition of the numerator and denominator and on how the reference measurement is used.

PI was assessed five minutes after salbutamol inhalation and was reported in the registry as a mean with full range as the dispersion measure. It was measured only in healthy volunteers and COPD participants in the lung-deposition study. The metered dose inhaler treatment was not radiolabelled, and the COPD physiology and asthma groups did not receive the radiolabelled treatment. The record therefore explains why PI data are unavailable for those treatments and groups. Numerical PI values and a treatment comparison are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, double-masked crossover study. These features address different aspects of design. Randomization assigns treatment order by chance, which can reduce systematic differences in the order in which treatments are received. Masking is intended to limit the influence of treatment knowledge on participant experience or outcome assessment. A crossover design exposes participants to more than one treatment, making within-participant comparisons possible in principle. These are general descriptions of the design concepts; the registry record does not report how masking was implemented, how treatment sequences were generated, or whether masking was maintained.

What does the crossover design imply?

In a crossover study, measurements from the same participant across treatment periods are related rather than independent. General statistical analysis should account for this within-participant correlation. It may also need to consider treatment period and sequence, because outcomes can vary over time or depend on treatment order. Residual effects from an earlier treatment can also complicate later-period interpretation; this is commonly called carryover. Whether such effects were relevant, how long any washout period lasted, and how these issues were handled are not reported in the registry record.

The group descriptions specify randomized crossover order for the listed treatments. They do not provide a sequence schedule or a statistical model. The registry therefore supports saying that crossover order was used, but not that a particular crossover analysis was performed. It also does not identify whether all participants completed all assigned periods or how incomplete treatment sequences were handled.

How should the Penetration Index be understood?

PI is a ratio based on regional radioaerosol counts, adjusted by the corresponding regional ratio from a Krypton ventilation scan. Ratios can be useful when the scientific question concerns relative distribution. Their interpretation depends on how the components are defined, whether the reference measurement is appropriate, and how variability in both components is handled. Here, the stated purpose is to express how deeply the inhaled aerosol reached into the lungs relative to the central region and the ventilation reference. This is a general explanation of ratio measures; no PI estimate is reported in the registry record.

The endpoint description states that the outcome was summarized as a mean with full range. A mean describes the average value, while a full range describes the lowest and highest observed values. The range can convey the spread of observed data but does not, by itself, quantify the precision of a mean estimate. In general, confidence intervals or standard errors are used to express estimate precision. Such uncertainty measures are not reported for PI in the registry record.

What can be inferred from the analysis reporting?

The registry lists zero analysis entries. This indicates that no inferential analysis results are recorded in the registry; it does not prove that no analyses were performed outside the registry. The record does not report a model, hypothesis test, confidence interval, adjustment strategy, or the statistical contrast used for the primary endpoint. It also does not state whether the primary comparison was between particle sizes, between an aerosol and the metered dose inhaler, or another contrast. The treatment descriptions alone do not specify which comparison was designated as primary.

In general, a p-value is a measure of how incompatible the observed data are with a specified null model, under its assumptions. It is not a measure of the size or clinical importance of an effect. A confidence interval gives an estimate alongside its uncertainty and can help show which effect sizes remain compatible with the data. Neither can be interpreted in this case because neither is reported for the primary outcome.

What do the planning assumptions mean?

The registry describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. Such calculations are prospective planning aids: they illustrate the participant count that would be needed under stated assumptions to detect a specified fraction of an observed effect. They are not observed power and do not show the probability that the completed study detected a true effect. The registry record does not report a numerical planning result or a stated fraction in the information available for this interpretation. The crossover design also means that a simple equal-allocation, two-arm illustration may not capture every feature of the actual study design.

In general, planning calculations depend on assumptions about the target effect, variability, allocation and analysis. A planning illustration based on an observed effect is especially dependent on how that effect was estimated. It should not be confused with a prespecified sample-size justification. The trial’s sample-size justification and any detailed statistical plan are not reported in the registry record. An interim analysis plan is also not reported in the registry record.

Why does the measurement method matter?

Radiolabelling is essential to the stated imaging approach because the gamma camera tracks the labelled salbutamol. The unlabelled metered dose inhaler treatment could not be assessed by this PI method according to the registry description. Consequently, the endpoint does not cover every treatment or study group. This is a measurement limitation, not a statistical finding. General statistical interpretation must follow the data that the endpoint can actually measure, without treating unmeasured outcomes as zero or as equivalent to measured outcomes.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures, including PI as the primary outcome and secondary outcomes named Scond and Sacin, both associated with multiple-breath nitrogen washout. It does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a plan for interpreting several tests together. In general, testing multiple outcomes or treatment contrasts can increase the chance of at least one apparently notable result arising by chance. Prespecified testing strategies or adjustments can address that issue, but such methods are not reported in the registry record.

The registry also does not identify a single primary treatment contrast for PI. The intervention descriptions include different aerosol particle sizes and a metered dose inhaler treatment, while the endpoint is unavailable for the unlabelled metered dose inhaler. Without a stated contrast and analysis plan, the intended family of comparisons cannot be determined. The absence of analysis entries means that adjusted or unadjusted inferential results are not reported in the registry record.

Missing-data handling is not reported in the registry record. The record does not say whether outcome data were missing, how incomplete crossover periods were handled, or whether any imputation or sensitivity analysis was used. Analysis populations, such as an intention-to-treat population or a per-protocol population, are also not reported in the registry record. These omissions matter because incomplete measurements or exclusions can affect which participants contribute to an estimate and how representative that estimate is.

In general, missingness can influence results when the probability of having an observed outcome is related to participant characteristics or outcomes. A transparent report would describe the extent and handling of missing data and specify the population used for each analysis. No such details are available in the registry record, so the implications of missingness cannot be assessed.

11. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events, other adverse events and deaths by study group. In the COPD lung-deposition group, 0 of 12 participants were reported as affected by a serious adverse event, 2 of 12 by another adverse event, and 0 deaths. In the healthy lung-deposition group, 0 of 12 were reported as affected by a serious adverse event, 0 of 12 by another adverse event, and 0 deaths. In the COPD lung-physiology group, the corresponding figures were 0 of 26 for serious adverse events, 0 of 26 for other adverse events, and 0 deaths. In the asthma lung-physiology group, they were 0 of 12 for serious adverse events, 0 of 12 for other adverse events, and 0 deaths.

These are descriptive registry counts. The “at risk” figures identify the group denominators recorded for the safety outcomes, while the affected figures record the number reported with an event. The two other adverse events in the COPD lung-deposition group are not listed as serious events in these figures. The registry does not identify their nature or timing in the information, and the list of top serious terms is empty.

Zero reported serious events or deaths should not be interpreted as proof that risk was absent. Event counts can be imprecise, particularly when based on limited group sizes, and the registry does not provide comparative risk estimates or confidence intervals. The record also does not state whether any event was considered related to treatment. These counts alone cannot establish causation or quantify differences in safety between treatments.

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

The record describes a randomized, double-masked crossover investigation of salbutamol aerosols and lung deposition in COPD and healthy participants, alongside a physiology study involving COPD and asthma groups. Its primary measurement is a radiotracer-based Penetration Index, designed to characterize the regional distribution of aerosol within the lungs. The endpoint and imaging method are described, as are the treatment regimens and group distinctions.

What the record does not establish is the observed PI value for any group or treatment, the size or direction of a treatment difference, or the uncertainty around an estimate. It gives no inferential results for the primary endpoint. It therefore cannot establish that a particular particle size led to greater or lesser peripheral deposition. Nor can a missing PI result for a treatment or group be treated as evidence of no deposition: the record explains that PI could not be calculated for the unlabelled metered dose inhaler treatment and was not measured in the COPD physiology and asthma groups.

The design could support within-participant treatment comparisons, in principle, but the registry does not report the analysis used, the primary contrast, or handling of period and sequence effects. It also does not report missing-data procedures or analysis populations. Those details are needed to evaluate how the design was translated into an estimate and how robust that estimate might be.

The safety figures describe few reported events in the listed categories, including no reported serious adverse events or deaths in any listed group. They are not comparative estimates and do not show that treatment-related risk was absent. The registry does not report whether events were judged related to treatment.

In short, the registry record documents a study question and a method for measuring lung deposition, but not the numerical findings needed to judge the result. A completed status is not itself a result. The record supports describing what was measured and in which groups, while the treatment effects, precision, and broader clinical meaning remain unreported.

13. Why This Trial Matters Statistically

This trial is statistically interesting because the primary endpoint links an imaging-based measure to a mechanistic question: where inhaled aerosol is distributed within the lung. The Penetration Index is not a direct measure of a patient’s overall clinical benefit. It is a ratio derived from regional radiotracer counts and a ventilation reference. Keeping the measurement distinct from clinical outcomes is important when interpreting mechanistic endpoints.

The crossover design is also relevant. In general, repeated treatment measurements within participants can reduce the influence of stable differences between people, but the analysis must respect the correlation among those measurements. Treatment order, period effects and possible carryover can matter. The record says treatments were given in randomized crossover order, yet does not describe the analysis or those design details. This makes the planned structure clear while leaving the statistical implementation uncertain.

The study also illustrates how measurement feasibility can shape the set of comparisons available. Radiolabelling enabled scintigraphic assessment for the lung-deposition groups, whereas the metered dose inhaler treatment was not labelled. Thus, the PI endpoint does not cover all treatments or groups. This distinction prevents an unmeasured value from being misread as a zero or as a direct comparison.

Finally, the record highlights the difference between registration details and reported results. It documents the endpoint, groups, treatment descriptions, and safety counts, but gives no numerical PI findings or inferential estimates. Without estimates and measures of uncertainty, readers cannot assess the magnitude or precision of a treatment contrast. The statistical significance, if any, and the clinical importance of the findings are not reported in the registry record.

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.

A central limitation of the registry record is the absence of numerical primary endpoint results. Although PI is defined and its assessment timing is given, no group values, treatment contrasts, or uncertainty estimates are reported. This prevents evaluation of the observed deposition pattern and its precision.

The endpoint is available only for healthy volunteers and COPD participants in the lung-deposition study. It was not measured in the COPD physiology or asthma groups, and no PI data are shown for the metered dose inhaler treatment because the drug was not radiolabelled. This restricts which groups and treatments can be compared using the primary measure. It also means that PI findings, if reported elsewhere, would not automatically generalize to every group or intervention in this study.

The registry does not identify the primary treatment contrast or provide an analysis model. Although treatment order was randomized in a crossover design, sequence details, washout intervals, period lengths, and handling of possible carryover are not reported in the registry record. The record also does not describe missing-data handling, analysis populations, or whether participants completed all treatment periods. These omissions limit assessment of bias and of whether the analysis matched the design.

The registry lists secondary outcomes but does not report their numerical results or a multiplicity strategy. Sample-size justification and interim analyses are not reported in the registry record. The safety information is limited to group-level counts; event descriptions, treatment relatedness and comparative safety estimates are not reported. These limitations are specific to what the registry record documents and should not be interpreted as proof that the unreported details or analyses do not exist elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Inhaler Lung Deposition in Chronic Obstructive Pulmonary Disease (COPD) — NCT01721291.
• Registry record last updated 2026-09-03; status last verified 2026-09.
• Results first posted 2023-03-06.
• 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

NCT01721291 is a completed Phase 4 randomized, double-masked crossover study sponsored by Imperial College London. The registry lists enrollment of 64 and describes lung-deposition groups involving COPD participants and healthy participants, alongside lung-physiology groups involving COPD participants and participants with asthma. Treatment descriptions include salbutamol aerosols with particle sizes of 1.5, 3.0 and 6.0 micron and a metered dose inhaler treatment.

The primary outcome is Penetration Index, assessed five minutes after inhalation using radiolabelled aerosol imaging and a Krypton ventilation reference. PI was measured only in the lung-deposition groups and was not available for the unlabelled metered dose inhaler treatment. Scond and Sacin are listed as secondary outcomes. Numerical endpoint results, inferential analyses, analysis populations and missing-data methods are not reported in the registry record. Safety counts are recorded by group, including no reported serious adverse events or deaths in the listed groups.