Study to Evaluate the Efficacy, Safety and Pharmacokinetics of PT001, PT003, and PT005 Following Chronic Dosing (7 Days) in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Efficacy, Safety and Pharmacokinetics of PT001, PT003, and PT005 Following Chronic Dosing (7 Days) in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) (NCT01085045), a randomized phase 2 study. The primary outcome is FEV1 AUC 0-12 on Day 7.

2. Clinical Question

3. Trial Design

This was a Phase 2, randomized, triple-masked, multicenter crossover study. Its official title describes a four-period, eight-treatment, placebo-controlled, incomplete-block design. Participants were enrolled with moderate to very severe COPD, and the registry reports total enrollment of 118. The study evaluated chronic dosing over 7 days and included two doses of PT003, two doses of PT005, one dose of PT001, placebo, Spiriva 18 μg, and Foradil 12 μg. The two active controls were open-label, while the test products and placebo were described as double-blind in the official title.

In a crossover design, participants receive more than one treatment over successive periods, rather than being assigned to only one treatment throughout. This structure can allow within-participant treatment comparisons, but interpretation depends on the sequence, period structure, and statistical handling of repeated observations. The registry record identifies the crossover and incomplete-block features but does not report the treatment sequences, washout details, or the statistical model used for the primary endpoint. Those details are not reported in the registry record.

The primary outcome was measured on Day 7 at pre-dose and at several post-dose time points extending through 12 hours. The registry reports least-squares means in liters and 95% confidence intervals for the arms. The primary analysis population is identified as Modified Intent to Treat, excluding the 4 sentinel patients. The listed arm counts differ, and the record does not explain the reasons for those differences. The study is marked completed; its start and primary completion are recorded as 2010-03 and 2010-11.

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: Part A: 4-period, 8-treatment, incomplete block cross-over. Subjects randomized to 1 of 48 sequences, each subject received 4 of 8 possible treatments. Part B: 4-period, 4-treatment, full cross-over. Each subject randomized to 1 of 24 sequences and each sequence was assigned to at least 1 subject.

Part A

Reasons for not completing this period:

Part B

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified Intent to Treat (MITT) Population - not including the 4 sentinel patients.

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: Analysis Population included all randomized participants. 118 plus 4 sentinel patients to make 122.

6. Primary Endpoint

The registry lists the primary outcome as FEV1 AUC 0-12 on Day 7, measured over "Pre-dose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, 10, 11.5, and 12 hours post-dose on Day 7.

The primary endpoint, FEV1 AUC 0-12 on Day 7, summarizes forced expiratory volume in one second (FEV1) over a 12-hour post-dose interval. FEV1 is the volume of air forcibly exhaled in the first second of a breath. The registry describes the endpoint as an area under the curve, normalized relative to baseline, following 7-day dose administration. Measurements were scheduled pre-dose and at post-dose times through 12 hours on Day 7.

An area-under-the-curve measure combines observations across the stated interval, so it represents the pattern of response over time rather than a single measurement. Normalization relative to baseline frames the result in relation to participants’ starting FEV1. In general, repeated measurements can capture how a continuous outcome changes over a dosing interval, although the details of the endpoint calculation and the model used to estimate least-squares means are not reported in the registry record.

The registry reports arm-level least-squares means in liters with 95% confidence intervals. These estimates describe the posted endpoint values and their uncertainty. They do not, by themselves, establish that one treatment differs from another: a comparison requires an estimated contrast and its uncertainty or a reported inferential test. For this endpoint, no two-arm comparison is reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a continuous primary endpoint as a least-squares mean with a 95% confidence interval. A least-squares mean is a model-based estimate of an average, generally adjusted for terms in a statistical model. The registry record does not specify the model terms, so the particular adjustments behind these estimates are not reported. The confidence interval describes uncertainty around each estimated arm mean under the analysis used. It is not a range that contains every participant’s measurement, and it is not a direct interval for the difference between two arms.

Why are arm estimates not enough to assess a treatment contrast?

A comparative question is answered by estimating a contrast, such as the difference between two treatment estimates, and quantifying uncertainty around that contrast. The registry gives separate estimates and confidence intervals for each primary endpoint arm, but does not report primary two-arm contrasts. Comparing the point estimates by eye does not account for the uncertainty in their relationship. In a crossover study, the within-participant structure can also matter: the uncertainty of a contrast may depend on paired observations and on how period and sequence effects are handled. The model and contrast details are not reported in the registry record.

What does a confidence interval communicate?

In general, a confidence interval represents the range of estimates reasonably compatible with the observed data under the statistical procedure and its assumptions. A narrower interval indicates greater precision than a wider interval. It does not measure the probability that a fixed true value lies in that particular interval, and it does not eliminate concerns about study design, missing observations, or model assumptions. For this primary endpoint, the reported 95% intervals relate to individual arm estimates rather than treatment differences.

How should the secondary binary comparisons be read?

The listed secondary comparisons use risk differences: the difference between the proportions with the specified outcome in two arms. A risk difference of 0 represents no difference in proportions. The GFF MDI 36/9.6 μg comparison has a risk difference of 0.003 and a confidence interval from -0.147 to 0.154; the GP MDI 36 μg comparison has a risk difference of -0.132 and a confidence interval from -0.308 to 0.045. Both intervals include 0, so the posted intervals do not exclude no difference. The unadjusted p-values are 0.965 and 0.15, respectively. These are recalculated unadjusted results, not reported sponsor analyses; no reported analyses are listed for this secondary endpoint.

In general, a p-value measures how incompatible the observed data are with a specified null model, assuming that model and the analysis assumptions hold. It does not measure the probability that a treatment is effective, or the size or importance of an effect. Because these p-values are unadjusted and relate to secondary comparisons, they provide limited support for broad claims about the full set of treatments and outcomes.

What are the planning figures for?

The sample-size figures are planning illustrations based on the observed secondary effect, not the trial’s own design or observed power. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The figures show participants per arm for 80% power and participants per arm for 90% power, for planning at 100%, 75%, and 50% of the observed effect. For example, planning for 100% of the observed effect in the GFF MDI 36/9.6 μg comparison gives 155,865 participants per arm for 80% power. This illustration reflects the very small observed risk difference and the stated assumptions; it is not a recommended enrollment target and does not describe the power of the completed trial. The registry record does not report the original sample-size justification.

Why can a crossover analysis require special care?

General statistical practice treats repeated observations from the same participant as related, rather than independent. A crossover analysis may need to account for treatment, period, sequence, and participant-level variation, depending on the design and analysis plan. Ignoring within-participant dependence can misstate uncertainty. An incomplete-block structure also means participants may not receive every treatment. The registry states that the study used an incomplete-block crossover design, but does not report the model, sequence allocation, period terms, or method for handling incomplete data. It is therefore not possible to verify those analytical choices from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies the primary endpoint and reports a list of secondary outcomes, but does not report the statistical analysis plan, a testing hierarchy, or a method for adjusting for multiple comparisons. With multiple treatments and outcomes, multiplicity is a concern because examining many contrasts can increase the chance of apparently notable results arising by chance. In general, a prespecified approach to multiplicity clarifies which hypotheses are confirmatory and how the overall error rate is controlled. Whether such a plan existed or was used is not reported in the registry record.

The secondary p-values described in the posted comparison results are unadjusted. They should therefore be interpreted as individual tests and not as controlling the probability of a false-positive conclusion across all treatment comparisons and outcomes. The record lists 12 posted secondary outcomes and reports 13 outcome measures overall, but the number of analyses is recorded as 0. The relationship between those entries and the complete set of analyses is not explained in the registry record.

The primary population is described as Modified Intent to Treat, excluding the 4 sentinel patients. The reasons for excluding those patients, the handling of missing measurements, and the rules for including participants or periods in each analysis are not reported in the registry record. In general, missing outcome data can affect both the estimate and its precision, especially if missingness is related to treatment or the outcome. The available record does not allow assessment of the extent or likely impact of missing data.

The registry identifies a crossover design but does not report the primary model or its handling of participant, period, and sequence effects. It also does not report interim analyses or the original sample-size justification. These omissions prevent a full assessment of the prespecified inferential framework, the treatment of incomplete observations, and whether the analysis followed a planned hierarchy.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: appendicitis perforated (2.3%), aortic aneurysm (1.7%), foreign body aspiration (1.7%), chronic obstructive pulmonary disease (1.6%), gastritis (1.6%).

The safety results report counts of participants at risk and counts affected for serious adverse events and other adverse events within each listed treatment group. For serious adverse events, the counts affected range from 0 to 2 across the groups. For other adverse events, the counts affected range from 4 to 17. These are descriptive counts. The registry does not provide a comparative statistical analysis of safety outcomes, so the counts alone do not establish whether differences between groups are meaningful.

The study used a crossover design, and the safety group counts are not necessarily independent participant groups. The record does not explain how exposure across treatment periods, repeated participation in groups, or duration of observation was handled in these summaries. Comparisons of raw counts should therefore be cautious. Death counts are not reported in the registry record.

The registry also lists serious adverse event terms and percentages, including Appendicitis perforated at 2.3%, Aortic aneurysm at 1.7%, Foreign Body Aspiration at 1.7%, Chronic obstructive pulmonary disease at 1.6%, Gastritis at 1.6%, and Chest pain at 1.6%. The record does not provide enough detail to infer from these entries how events were distributed across treatment periods or whether they were judged related to treatment. These summaries are descriptive and should not be interpreted as causal comparisons.

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

The posted results show arm-level least-squares mean estimates for the primary Day 7 FEV1 AUC 0-12 endpoint, with 95% confidence intervals. They describe the endpoint as estimated in each arm and convey the precision of those arm estimates. They do not include the primary treatment contrasts needed to assess the study’s main comparative question. As a result, the registry record does not establish whether a study treatment differed from its components, placebo, or active controls on the primary endpoint.

The available secondary binary comparisons provide estimates for a different outcome at a different time point. Their confidence intervals include no difference, and the p-values are unadjusted. These results neither prove equivalence nor establish a treatment effect. They also do not answer the primary Day 7 question. Sample-size planning illustrations based on the observed effect are not observed power and do not show how adequately the completed trial was powered for its primary objective.

In general, an estimate should be interpreted together with its uncertainty, the design, the analysis population, and the completeness of reporting. Here, important details—including the primary comparison model, multiplicity approach, missing-data handling, and sample-size justification—are not reported in the registry record. That limits how strongly the posted numbers can support a conclusion.

The registry describes a short, 7-day dosing study in patients with moderate to very severe COPD. Its results should not be extended beyond the recorded population, treatment period, endpoints, or analysis. The estimates do not establish long-term effects, nor do the safety summaries establish comparative safety. The appropriate reading is descriptive and cautious: the registry reports numerical arm estimates and selected secondary results, while leaving the primary comparative inference and several key analytical details unreported.

13. Why This Trial Matters Statistically

This trial illustrates a central distinction in clinical biostatistics: a set of arm-level estimates is not the same as a set of treatment comparisons. The primary endpoint results are reported with confidence intervals for each arm, but the registry does not report contrasts between arms. Readers can see the estimated endpoint values, yet cannot use those values alone to determine the uncertainty around a treatment difference or assess the primary hypothesis inferentially.

The crossover structure makes the distinction especially important. In general, within-participant comparisons can use information about how the same participant responds under different treatments, but that requires appropriate modeling of the repeated observations and design structure. The registry identifies an incomplete-block crossover but does not describe the statistical model or the handling of period and sequence effects. This means that the necessary analytical details for judging the primary comparison are not available in the registry record.

The record also demonstrates why secondary findings and planning calculations need careful framing. The available secondary comparisons are unadjusted and imprecise, while the sample-size figures are planning illustrations based on observed effects rather than a description of the completed trial’s power. Neither should be mistaken for a confirmatory analysis of the primary question. Clear reporting of contrasts, uncertainty, multiplicity, analysis populations, and missing-data methods is essential for readers to distinguish descriptive patterns from supported statistical conclusions.

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.

Several trial-specific reporting limitations constrain interpretation. The registry reports primary arm estimates but no two-arm comparisons for the primary endpoint. It does not describe the statistical model underlying the least-squares means or explain how the crossover’s repeated observations, periods, sequences, and incomplete treatment blocks were handled. The arm-specific primary sample sizes vary, and the reasons for those counts are not reported in the registry record.

The Modified Intent to Treat population excludes the 4 sentinel patients, but the record does not explain the exclusion rationale or provide further details about the analysis population. Missing-data extent, patterns, and handling are not reported. Without those details, the effect of incomplete measurements on estimates and precision cannot be assessed.

The registry does not report a multiplicity strategy, a hierarchy for secondary endpoints, interim analyses, or the original sample-size justification. The available secondary comparisons are unadjusted recalculations, and the number of reported analyses is recorded as 0. The registry does not explain the relationship between this entry and the posted secondary results. These limitations make the secondary findings difficult to treat as confirmatory.

Safety summaries are descriptive counts, with no reported comparative analysis. The record does not explain how the crossover exposure structure was reflected in those summaries, and death counts are not reported in the registry record. The treatment-name labels in the primary results are also not directly mapped to all intervention names in the study description. These reporting gaps do not invalidate the posted estimates, but they limit independent assessment and the strength of conclusions that can be drawn from them.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Evaluate the Efficacy, Safety and Pharmacokinetics of PT001, PT003, and PT005 Following Chronic Dosing (7 Days) in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) — NCT01085045.
• Registry record last updated 2017-04-26; status last verified 2017-03.
• Results first posted 2017-04-26.
• 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 2 study randomized 118 patients with moderate to very severe COPD in a triple-masked, multicenter, four-period, eight-treatment, incomplete-block crossover design. It evaluated two PT003 doses, two PT005 doses, one PT001 dose, placebo, and two open-label active controls following 7 days of dosing. The primary outcome was normalized FEV1 AUC 0-12 on Day 7, reported as arm-level least-squares means with 95% confidence intervals in a Modified Intent to Treat population excluding the 4 sentinel patients.

The registry does not report primary pairwise comparisons, the analysis model, multiplicity procedures, or missing-data methods. Selected secondary binary comparisons are unadjusted and have confidence intervals that include no difference. Safety results are descriptive counts. These registry results characterize posted estimates but do not provide a complete inferential assessment of the primary treatment question.