Crossover Study to Assess the Efficacy of PT003 With and Without a Valved Holding Chamber in Subjects With Moderate to Severe COPD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Crossover Study to Assess the Efficacy of PT003 With and Without a Valved Holding Chamber in Subjects With Moderate to Severe COPD (NCT02454959), a randomized phase 3 study. The primary outcome is Area Under the Curve for Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) From 0 to 12 Hours (AUC0-12) on Day 8.

2. Clinical Question

The central comparison is about delivery configuration, not about two different drug combinations: both conditions used PT003, while the presence of the valved holding chamber differed. In a crossover study, participants receive both conditions in separate periods, so each participant can contribute information under both configurations. The record identifies a two-period design but does not report the treatment sequence, period-specific results, or details of any interval between periods.

The endpoint focuses on the change in forced expiratory volume in 1 second (FEV1) across a 12-hour period after dosing on Day 8. It is a measure of the lung-function response over time, rather than a single measurement at one post-dose time. The primary analysis compared the adjusted means reported for the two configurations. Its unadjusted contrast is accompanied by a confidence interval that spans zero, so the posted summary does not precisely distinguish the direction of the contrast.

3. Trial Design

The registry describes NCT02454959 as a completed, randomized, Phase III, two-period, open-label, multicenter crossover study. It enrolled 80 participants and studied PT003 in people with COPD. The official title describes the disease severity as moderate to very severe, while the brief summary says moderate to severe. The sponsor was Pearl Therapeutics, Inc. The registry lists a start date of 2015-05-01 and a primary completion date of 2016-03-25.

Both study conditions used glycopyrronium and formoterol fumarate delivered by metered dose inhaler. The difference was whether the inhaler was used with an Aerochamber Plus Valved Holding Chamber. One condition was PT003 with the chamber and the other was PT003 without it. The design therefore compares two ways of using the same inhaled treatment, rather than comparing PT003 with a different drug or with no treatment.

In a crossover design, participants receive more than one study condition in different periods. This can make within-participant comparisons informative because each participant experiences both conditions. The registry identifies two periods, but the treatment sequence, any washout interval, and the period-specific participant counts are not reported in the registry record. The open-label designation means the study is described as having no masking; the registry does not state whether any particular outcome assessment was masked.

The primary endpoint was assessed after 7 days of treatment and used the Modified-Intent-to-Treat (MITT) Population. The reported group summaries include 67 participants for the with-chamber condition and 68 for the without-chamber condition. The registry does not explain the relationship between these analysis counts and the total enrollment of 80, or report the original sample-size rationale, allocation sequence details, or the full statistical analysis plan.

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: Subject received one week of study treatment for each of the treatment periods, separated by a washout period of 7-14 days between treatments. Intent-to-treat (ITT) Population is used for Participant Flow. By-sequence tabulations of the data were not pre-specified.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The primary analysis used the Modified-Intent-to-Treat (MITT) Population.

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: The Modified-Intent-to-Treat (MITT) Population is a subset of the Intent-to-Treat (ITT) Population including subjects who received treatment and had post-treatment efficacy data for both treatment periods and is used for the baseline characteristics.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Curve for Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) From 0 to 12 Hours (AUC0-12) on Day 8, measured over 7 days of treatment.

The primary endpoint was the area under the curve (AUC) for change from baseline in FEV1 from 0 to 12 hours on Day 8, measured in liters. The registry says it was assessed after 7 days of treatment. FEV1 is the volume of air forcibly exhaled in the first second of a breathing maneuver. The endpoint combines measurements over a defined post-dose interval rather than relying on a single time point.

The AUC was calculated using the trapezoidal rule from FEV1 assessments taken pre-dose and at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 11.5 hours, and 12 hours after dosing. In general, the trapezoidal rule estimates the area under a curve by connecting observed points with straight-line segments and summing the resulting areas. This provides a way to represent the response over the full assessment interval, while depending on the measurements at the specified times.

The registry reports that the primary outcome was modeled conditionally on baseline FEV1. In general, accounting for baseline can improve the comparison by recognizing that starting lung function may differ among participants. The reported outcome statistic is a least-squares mean, which is a model-based mean rather than simply the arithmetic average of individual observations. The registry does not report the full model specification or the assumptions used to fit it.

7. Results Posted in the Registry

• GFF MDI (PT003) Without Aerochamber: mean 1.52 versus 1.54 on control; difference -0.02 (95% CI -0.09 to 0.04), standardized effect d = -0.12; z-test p = 0.494.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

AUC0-12 on Day 8

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • GFF MDI (PT003) Without Aerochamber: mean 111.39 versus 128.00 on control; difference -16.61 (95% CI -44.54 to 11.32), standardized effect d = -0.22; z-test p = 0.244.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between GFF MDI (PT003) Without Aerochamber and the control. The interval gives the range of effects that remain compatible with the data.

Cmax on Day 8

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • GFF MDI (PT003) Without Aerochamber: mean 26.55 versus 34.03 on control; difference -7.48 (95% CI -14.02 to -0.94), standardized effect d = -0.40; z-test p = 0.025.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for GFF MDI (PT003) Without Aerochamber than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary results address pharmacokinetic measures on Day 8 rather than the primary lung-function response. Across the posted summaries, the direction of the comparison is lower without the chamber for both AUC0-12 and Cmax. Their uncertainty differs: the AUC0-12 interval includes zero, while the Cmax interval does not in the unadjusted summary calculation. These are distinct measures, so their estimates should not be treated as interchangeable evidence about the primary FEV1 outcome.

The primary endpoint concerns change from baseline in FEV1 over 0 to 12 hours. Pharmacokinetic AUC and maximum concentration describe drug concentration, not FEV1. They may provide a different perspective on exposure, but they do not directly answer the primary clinical measurement question. The Cmax summary’s interval therefore does not negate or replace the primary result, whose contrast interval includes zero. Nor does the primary result establish a particular pharmacokinetic explanation.

The registry lists Tmax on Day 8 among the secondary outcomes, but a numerical Tmax result is not reported in the registry record. Although several secondary outcomes are listed, only two secondary outcome summaries are available in the posted results. The registry does not report secondary analyses. This incomplete reporting makes it difficult to assess the full set of planned secondary findings or determine whether all intended outcomes are represented.

Unadjusted secondary results carry less inferential weight when several outcomes are examined, because the chance of at least one apparently notable result can increase with repeated testing. In general, multiplicity procedures address that issue by controlling how evidence is assessed across outcomes. The registry does not report whether such a procedure was specified or used. The secondary estimates are best read as supportive descriptive information, not as stand-alone confirmation of the primary comparison or as a basis for a definitive overall conclusion.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• AUC0-12 on Day 8
• AUC0-12 on Day 8
• Cmax on Day 8
• Cmax on Day 8
• Tmax on Day 8
• Tmax on Day 8

9. Statistical Interpretation

10. Statistical Methods Explained

The primary summary uses a least-squares mean and a standard error. A least-squares mean is a model-based estimate of an average, potentially adjusted for terms in the model. The registry says the primary endpoint was modeled conditionally on baseline FEV1, but does not report the full model formula, the covariates beyond baseline, or how the crossover periods and treatment sequence were represented. The reported means should therefore be understood as the registry’s model-based summaries, without assuming details that are not described.

What does the primary contrast represent?

The contrast compares the without-chamber condition with the with-chamber condition. Its sign follows that ordering: a negative estimate means the reported value was lower without the chamber, while a positive estimate would mean it was higher without the chamber. The unadjusted recalculation is -0.022 liters. It uses the posted estimates and their summary uncertainty; it is not a newly fitted crossover model. The registry does not report a sponsor analysis output for the comparison, and the summary-statistic calculation cannot account fully for participant-level pairing.

Why does the crossover structure matter?

In general, crossover studies compare conditions within the same participants, which can remove some between-person variability from the treatment contrast. The precision of such a comparison depends on how responses under the two conditions relate within individuals. A calculation that treats the posted group summaries as if they were independent cannot recover that relationship. The primary estimates include standard errors, but the registry does not provide the within-person covariance, period effects, sequence information, or a detailed model output needed to reconstruct a paired analysis. The posted recalculation is consequently a descriptive, unadjusted comparison, not a replacement for a full analysis of the randomized crossover design.

What does the standard error tell readers?

In general, a standard error describes the precision of an estimated mean: smaller standard errors indicate less sampling uncertainty around that estimate, under the model used. It is not the same as the standard deviation, which describes spread among observations. The primary outcome reports standard errors for the least-squares means. By contrast, the secondary pharmacokinetic summaries report standard deviations, which describe participant-to-participant variation in the measured values. These dispersion measures answer different questions and should not be treated as interchangeable.

How should the confidence interval and p-value be read?

In general, a confidence interval gives a range of values reasonably compatible with the data and the method used to calculate it. It communicates both the estimated direction and the uncertainty around the estimate. A confidence interval that crosses zero for a difference does not establish that the true difference is zero; it indicates that the posted data do not rule out values on either side of zero at that confidence level. The primary interval runs from -0.085 to 0.041 liters. The unadjusted p-value of 0.494 measures how incompatible the data are with a specified no-difference model under the calculation’s assumptions. It is not the probability that the no-difference model is true.

These are unadjusted quantities. The registry does not report multiplicity control for the primary and secondary outcomes, or a sponsor-reported p-value for the primary comparison. No adjustment for multiple comparisons should be assumed. Since the primary endpoint is identified as primary, it is the principal endpoint for interpretation, but the registry record does not describe a prespecified hierarchy or testing procedure.

What do the secondary measures add?

The posted secondary summaries include pharmacokinetic AUC0-12 and Cmax on Day 8. These are not the same outcome as the primary FEV1 AUC: the secondary AUC is expressed in h*pg/mL, and Cmax is expressed in pg/mL. In general, AUC represents cumulative exposure over a period, while Cmax is the maximum measured concentration. The registry also lists Tmax among the secondary outcomes, but a numerical Tmax result is not reported in the registry record. There are no reported secondary analyses in the registry. The available summary comparisons are therefore not a complete account of all possible model-based or prespecified analyses.

Over-dispersion is a general concern when outcome variability exceeds what a chosen model assumes. If that occurs and is not handled appropriately, uncertainty estimates can be too small and inferential conclusions too confident. The registry summaries do not report a dispersion assessment or model diagnostics, so the presence or handling of over-dispersion cannot be evaluated for this trial. More generally, model assumptions should be checked against participant-level data and the design; summary values alone do not permit those checks.

Finally, randomized assignment supports a planned comparison between conditions, but it does not by itself resolve missing-data problems, deviations from treatment, or incomplete outcome reporting. The registry identifies an MITT primary population but does not report its detailed definition, analysis exclusions, missing-data strategy, or sensitivity analyses. Those omissions limit how fully the posted results can be audited or reproduced.

11. Confidence Intervals and Precision

The primary unadjusted contrast is -0.022 liters, with a 95% confidence interval from -0.085 to 0.041 liters. The interval crosses zero, so the posted summary is compatible with a difference in either direction. Its width shows that the estimate is not precise enough to tightly locate the contrast. The interval does not mean that all values inside it are equally likely, and it does not establish equivalence between the two configurations.

The individual least-squares means are reported with standard errors of 0.023 liters for the with-chamber condition and 0.023 liters for the without-chamber condition. A standard error describes uncertainty in an estimated mean, while the confidence interval for the contrast describes uncertainty in the between-condition comparison. The latter is the more direct measure for assessing the primary question. The registry does not provide confidence intervals for the two individual means.

The secondary estimates have their own intervals and should be read outcome by outcome. The AUC0-12 comparison has an interval from -44.54 to 11.32 h*pg/mL, which includes zero. The Cmax comparison has an interval from -14.02 to -0.944 pg/mL, which does not include zero in the unadjusted calculation. These intervals describe the summary-statistic comparisons, not a multiplicity-adjusted set of inferences or necessarily the full crossover model.

In general, precision depends on the amount and variability of information, the analysis model, and—in crossover studies—the relationship between measurements from the same participant. The registry does not provide enough detail to assess all of these features. The available intervals are useful for displaying uncertainty, but should be interpreted with the limitations of the reported summaries in mind.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not the trial’s original design calculation. For the primary endpoint, the illustration uses 1,134 participants per arm for 80% power and 1,517 participants per arm for 90% power when planning for 100% of the observed effect. Planning for 75% of the observed effect gives 2,015 participants per arm for 80% power and 2,697 participants per arm for 90% power. Planning for 50% of the observed effect gives 4,533 participants per arm for 80% power and 6,068 participants per arm for 90% power.

All figures for these continuous outcomes are participants per arm, not total events. The listed planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The sample-size assumptions used in the trial’s original design are not reported in the registry record.

In general, the 80% power column describes an assumed chance of detecting the stated effect under the planning model if that effect is present; the 90% column uses a higher target chance of detection. Smaller effects require more participants to detect under otherwise similar assumptions, which is why the figures increase as the planned fraction of the observed effect decreases. These are planning illustrations, not observed power. They do not show the probability that the trial’s result is correct, and they should not be interpreted as a retrospective measure of the trial’s success.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.022; pooled standard deviation σ = 0.187.
2. n = 2 × (1.96 + 0.842)² × 0.187² / -0.022² = 1,133.1, rounded up to 1,134 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.022                      # observed difference in means
sigma <- 0.186909847594554                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2454959)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 1,134 (80% power), 1,517 (90% power)
 75% of observed effect: n per arm = 2,015 (80% power), 2,697 (90% power)
 50% of observed effect: n per arm = 4,533 (80% power), 6,068 (90% power)
power.t.test: 1134 
Simulated power at n = 1,134 per arm: 0.800 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary endpoint and lists multiple secondary outcomes. It does not report a multiplicity adjustment, a testing hierarchy, or rules describing how the primary and secondary results were to be interpreted together. When several outcomes are tested, unadjusted p-values do not account for the increased chance of at least one small p-value arising by chance. This general issue is relevant to the secondary findings, particularly the unadjusted Cmax comparison. No claim about formal multiplicity control can be made from the registry record.

The registry lists 80 enrolled participants, while the primary outcome summaries include 67 participants in the with-chamber condition and 68 in the without-chamber condition. It does not explain the difference between enrollment and these analysis counts, whether all randomized participants contributed data to each period, or why the counts differ between conditions. In a crossover study, condition-specific counts can also be affected by availability of measurements in each period, but the record does not describe the reasons in this trial.

The primary analysis population is identified as Modified-Intent-to-Treat (MITT), but the eligibility criteria for that analysis population are not reported in the registry record. The registry also does not report a missing-data method, a description of missing observations, an imputation approach, or sensitivity analyses. It is therefore not possible to assess from the posted summary how missing data might affect the comparison.

Other analysis details are also unreported: the original sample-size justification, the crossover model specification, handling of period or sequence effects, and any interim analyses. These items should not be inferred from the design label or from the sample-size planning illustrations. The available data allow a limited reading of the posted estimates and their uncertainty, but do not provide a full account of the analysis plan or its implementation.

15. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pancreatitis (1.4%), respiratory distress (1.3%), deep vein thrombosis (1.3%).

The registry reports serious adverse events among 74 participants at risk in the with-chamber condition, of whom 1 was affected, and among 78 participants at risk in the without-chamber condition, of whom 2 were affected. For other adverse events, 3 of 74 participants at risk were affected with the chamber, compared with 8 of 78 at risk without it. These are counts in the registry’s condition-specific groups; they should not be interpreted as a randomized comparison of risk without further detail about exposure, event definitions, and the crossover analysis.

The registry lists pancreatitis at 1.4%, respiratory distress at 1.3%, and deep vein thrombosis at 1.3% among the top serious adverse event terms. The record does not indicate which treatment condition each term corresponds to, so these percentages should not be assigned to a particular configuration. Deaths are not reported in the registry record.

Adverse event counts describe events recorded during the study and do not by themselves establish that a study condition caused an event. The record does not provide enough information to assess event timing, duration, severity beyond the serious classification, or comparative exposure time. These figures are descriptive safety information, not proof of a causal difference between conditions.

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

The posted primary result describes a modest estimated difference in the day-8 FEV1 AUC between use of PT003 with and without a valved holding chamber. The unadjusted contrast is -0.022 liters for without chamber versus with chamber, and its confidence interval includes zero. The data summarized in the registry therefore do not precisely establish the direction of the difference. This is a statement about the estimate and its uncertainty, not a conclusion that the conditions are the same.

A non-significant unadjusted p-value does not prove equivalence or demonstrate that a clinically important difference is absent. Equivalence requires an appropriate design, a prespecified margin defining what differences would count as sufficiently similar, and an analysis that evaluates that margin. The registry does not report an equivalence margin or an equivalence analysis. The reported result should therefore be read as an uncertain comparison, not as evidence that the two configurations are interchangeable.

The primary endpoint captures a measured lung-function response over a 12-hour period after dosing on Day 8, following 7 days of treatment. It does not describe every aspect of COPD, patient experience, longer-term outcomes, or the effects of use outside the study conditions. The pharmacokinetic summaries are separate outcomes and should not be used to infer the primary lung-function result or a mechanism for it.

The crossover design allows participants to receive both conditions, but the registry does not report the details needed to reproduce a participant-level analysis. The posted unadjusted recalculation is consequently limited compared with a complete analysis that incorporates within-participant information and the study periods. Open-label conduct, unreported missing-data handling, and incomplete secondary outcome reporting also limit interpretation.

These results are a record of the measured outcomes and analysis summaries reported for this study. They do not, on their own, settle how the delivery configurations compare in other populations, settings, or durations of use. No treatment recommendation follows from this statistical interpretation.

17. Why This Trial Matters Statistically

This trial is statistically interesting because it compares two delivery configurations for the same inhaled treatment in a randomized crossover design. A crossover can support within-participant comparisons, but that advantage depends on analysis that respects the pairing of observations. The registry reports model-based primary means but does not provide the participant-level relationship, period effects, sequence, or full model specification. The contrast illustrates why the design label alone is not enough to reconstruct the analysis.

The primary endpoint also illustrates a distinction between a point estimate and precision. The estimated contrast is close to zero, but the confidence interval spans values on both sides of zero. A single p-value cannot convey this range of plausible effects. Reading the estimate, interval, and analysis context together gives a more informative account than treating a threshold as a complete answer.

The record further shows how secondary pharmacokinetic outcomes can complement, but not substitute for, a primary physiological endpoint. The secondary summaries vary in their uncertainty, and the registry does not describe multiplicity control or report a numerical Tmax result. That makes clear why secondary findings require careful qualification when several endpoints are listed and not all planned analyses are documented.

Finally, the difference between total enrollment and the condition-specific primary analysis counts underscores the importance of reporting analysis populations and missing data. The MITT designation is given, but its operational definition is not. For biostatisticians and clinical researchers, these reporting gaps matter because they affect reproducibility, interpretation of precision, and confidence in how closely a posted summary reflects the randomized crossover comparison.

18. 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.

Several limitations specific to this registry record constrain interpretation. Although the study is described as a two-period crossover, the treatment sequence and any washout interval are not reported. Period-specific results, sequence effects, and the within-participant association between responses are also absent. As a result, the unadjusted summary-statistic comparison cannot reproduce a full analysis of the crossover design.

The registry provides primary least-squares means and standard errors, but not the full statistical model, complete sponsor analysis, or detailed diagnostics. It identifies the MITT Population without defining it. The analysis counts differ between conditions and are below the total enrollment, but the reasons are not reported in the registry record. Missing-data methods, exclusions, and sensitivity analyses are likewise not reported.

The open-label design is a further consideration. The registry states that masking was absent but does not say whether any specific measurement or analysis was otherwise protected from knowledge of treatment condition. The primary endpoint is an objective lung-function measure, but the available record does not provide enough detail to evaluate all potential sources of measurement or conduct-related bias.

Secondary reporting is incomplete: Tmax is listed but its numerical result is not reported in the registry record, and no secondary analyses are reported. Multiplicity procedures and the original sample-size justification are also not reported. The observed-effect planning illustrations should not be mistaken for the trial’s original design assumptions. Finally, adverse-event counts are descriptive and do not include enough detail to attribute events or compare exposure-adjusted safety between configurations.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Crossover Study to Assess the Efficacy of PT003 With and Without a Valved Holding Chamber in Subjects With Moderate to Severe COPD — NCT02454959.
• Registry record last updated 2017-04-19; status last verified 2017-03.
• Results first posted 2017-04-19.
• 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.

22. Record Summary

NCT02454959 was a completed randomized Phase III, open-label, two-period crossover study of PT003 used with versus without an Aerochamber Plus Valved Holding Chamber in people with COPD. The primary endpoint was the day-8 AUC for change from baseline in FEV1 from 0 to 12 hours after dosing. The registry reports a primary least-squares mean of 1.538 liters with the chamber and 1.516 liters without it. The unadjusted recalculated contrast was -0.022 liters, with a 95% confidence interval from -0.085 to 0.041 liters.

The interval includes zero, and the registry does not report the full crossover model or enough detail to reconstruct it. Secondary pharmacokinetic summaries are available for AUC0-12 and Cmax; a numerical Tmax result is not reported in the registry record. The record also reports adverse event counts, but these are descriptive and do not establish causation. Missing-data methods, multiplicity procedures, and the original sample-size rationale are not reported in the registry record.