Extension Study to Evaluate the Safety and Efficacy of PT003, PT001, and PT005 in Subjects With Moderate to Very Severe COPD, With Spiriva® Handihaler® (PINNACLE 3): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Extension Study to Evaluate the Safety and Efficacy of PT003, PT001, and PT005 in Subjects With Moderate to Very Severe COPD, With Spiriva® Handihaler® (PINNACLE 3) (NCT01970878), a randomized phase 3 study. The primary outcome is Change From Baseline in Morning -Pre-dose Trough FEV1 Over 52 Weeks.

2. Clinical Question

The clinical question is about lung function over time in a population continuing from earlier studies, rather than a new sample recruited independently of those studies. Eligibility required completion of PT003006 or PT003007. The registry describes the extension as a study of long-term safety and tolerability, while also reporting efficacy outcomes, including the primary FEV1 measure.

The reported endpoint is a change from baseline, averaged using a model across post-baseline visits from Week 2 through Week 52. This makes the stated result different from a single-visit measurement: it represents an average across the specified follow-up visits. The record gives a mean change for each arm, but does not give a formal contrast between any treatment and the active control. Therefore the arm estimates describe change within each group; they do not, by themselves, quantify the difference between groups.

3. Trial Design

The registry describes a completed Phase 3, randomized, parallel-group study with active control. Its official title characterizes it as a 28-week, multi-center safety extension, and the brief description identifies it as an extension of the pivotal 24-week studies PT003006 and PT003007. Participants had to complete one of those lead-in studies to be eligible. The stated overall observation period, including the lead-in studies, was 52 weeks.

The treatment groups were GFF MDI (PT003), GP MDI (PT001), FF MDI (PT005), and open-label tiotropium bromide inhalation (Spiriva® Handihaler®). The registry identifies randomized allocation, a parallel model, and triple masking. Its study description also uses the term double-blind, while the tiotropium comparator is explicitly described as open-label. The record does not explain the terminology or specify which groups or roles were masked.

Registry enrollment is 892. The primary endpoint results list arm populations of 1021 for GFF MDI, 872 for GP MDI, 871 for FF MDI, and 445 for open-label tiotropium. The endpoint population is described as participants in the ITT population from the lead-in studies who had data for the parameter. The basis for the difference between the enrollment figure and the endpoint arm counts is not reported in the registry record; these figures should not be treated as interchangeable measures of one analysis population.

The study status is completed. Its recorded start was 2013-11, and primary completion was 2015-03. The registry does not report the allocation ratio, detailed eligibility criteria beyond completion of a lead-in study, or the reasons for any differences in the arm-specific populations.

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: Study PT003008 was an extension of Studies NCT01854645 and NCT01854658. A proportion of subjects on active treatment were randomly invited to participate. Analysis of Study PT003008 included all subjects enrolled in the lead-in studies to avoid bias. Hence, the number analyzed will be greater than the 892 subjects enrolled into the extension.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Subjects in the ITT population from the lead-in studies who had data for the parameter.

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: Baseline population includes all subjects enrolled into active treatment arms for the lead-in Studies PT003006 \& PT003007

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Morning -Pre-dose Trough FEV1 Over 52 Weeks, measured over Baseline and Weeks 2 to 52.

The primary endpoint is change from baseline in morning pre-dose trough FEV1 over 52 weeks, measured in liters. FEV1 is the volume of air that can be forcefully exhaled in the first second of an effort. Morning pre-dose trough measurement refers to assessment before the next dose, and the registry defines the reported result as a model-based average of measurements from Week 2 through Week 52 inclusive.

Rather than reporting a separate change at each follow-up visit, the registry describes a model-based average across the post-baseline visits. The reported value is the difference between baseline and that average post-baseline FEV1. The arm estimates are least-squares means, with 95% confidence intervals. The stated analysis population is the ITT population from the lead-in studies with data for the parameter.

Repeated measurements can describe lung function over the follow-up period rather than at one isolated visit. A model-based average can incorporate the planned repeated-visit structure, but its interpretation depends on the statistical model and how missing observations were handled. Those details are not reported in the registry record. The endpoint is one measure among the study’s outcomes; the registry also lists patient-reported breathlessness, peak post-dose FEV1 change, health status, and rescue Ventolin use as secondary outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Continuous outcomes, such as FEV1 measured in liters, are commonly summarized with a mean or model-based mean. Here, the registry identifies the parameter as a least-squares mean. In general, a least-squares mean is an estimate derived from a statistical model; depending on the model, it may account for specified design factors or repeated observations. The registry does not report the model specification, so it is not possible to say which factors were included or how the model treated correlation between repeated measurements.

What does the reported change represent?

The endpoint is defined as the change between baseline and a model-based average of FEV1 measurements from Week 2 through Week 52. A positive arm estimate therefore describes an estimated increase from baseline for that arm on the stated scale. It does not automatically describe a causal treatment effect relative to another arm. A relative effect would require a direct contrast between arms, which is not reported in the registry record.

Repeated measurements can provide information over the course of follow-up, but observations from the same participant are generally related rather than independent. In general, a statistical model for repeated measurements needs to account for that dependence to produce appropriate estimates and uncertainty. The record says that a model-based average was calculated, but does not report the model family, covariance structure, estimation method, or assumptions used.

How should the confidence intervals be read?

A 95% confidence interval describes uncertainty in an estimated quantity under the statistical procedure and its assumptions. In general, it is not a range that contains 95% of individual participants’ measurements, and it is not a guarantee that the true value lies inside the interval. In this study the intervals accompany arm-specific least-squares mean changes. They quantify uncertainty around those estimated changes, not uncertainty around an unreported between-arm difference.

The registry gives the following arm estimates: GFF MDI, 0.133 liters, with a 95% confidence interval of 0.122 to 0.144; GP MDI, 0.076 liters, with a 95% confidence interval of 0.064 to 0.088; FF MDI, 0.068 liters, with a 95% confidence interval of 0.056 to 0.08; and open-label Spiriva® Handihaler®, 0.107 liters, with a 95% confidence interval of 0.091 to 0.124. The overlap or separation of arm-specific intervals is not a substitute for a formal comparison. A direct contrast can have a different uncertainty calculation, particularly when estimates share model information or participants are measured repeatedly.

What does the planning framework mean?

General sample-size planning asks how many participants may be needed to detect a specified effect under a chosen design and statistical assumptions. The record’s planning description specifies a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. Such values are planning illustrations, not results from random assignment and not observed power. They do not establish that the original trial was designed around those assumptions. The trial’s own sample-size justification is not reported in the registry record.

In general, a planning illustration based on an observed effect should be interpreted cautiously: the observed estimate is uncertain, and the planning assumptions may not match the study’s actual design or analysis. The registry does not report a design rationale, target power, or the assumptions used for the trial’s original enrollment decision. No separate conclusion about the adequacy of the study’s sample size can be drawn from the listed endpoint estimates alone.

What can be inferred about the statistical tests?

The registry record does not report primary-endpoint p-values, treatment contrasts, or a detailed statistical analysis plan. The presence of confidence intervals for each arm does not reveal whether a planned between-group test was conducted, which comparison was primary, or whether adjustment for multiple comparisons was used. The statistical plan, including any interim analyses, is not reported in the registry record.

For a continuous endpoint, general model checks can address whether the model’s assumptions are plausible, including the form of residual variation and the handling of repeated measures. The registry does not report diagnostic checks or sensitivity analyses. Over-dispersion is mainly a concern in some count-data models when observed variability exceeds the model’s assumed variability; it is not a feature that can be assessed from these arm-level continuous estimates alone. No claim about over-dispersion or model adequacy can be made from the registry results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and four secondary outcomes: SAC TDI Focal Score over 52 weeks, peak change from baseline in FEV1 within 2 hours post-dosing, change from baseline in SGRQ total score, and change from baseline in average daily rescue Ventolin use. Detailed numerical results for those secondary outcomes are not reported in the registry record. The record does not describe a multiplicity procedure or say how interpretation was to account for testing more than one outcome or comparison.

Multiplicity matters in general because evaluating multiple outcomes or treatment contrasts can increase the chance that at least one result appears statistically notable by chance. Methods such as prespecifying a primary comparison or adjusting significance criteria can address that issue, but the registry does not report whether or how such methods were used. It also does not report the planned hierarchy of comparisons or whether any outcomes were designated as exploratory.

The primary endpoint description identifies the ITT population from the lead-in studies who had data for the parameter. The model-based endpoint averages measurements over visits from Week 2 to Week 52. The record does not explain how participants without endpoint data, participants with incomplete follow-up, or missing measurements at individual visits were handled. It does not report imputation methods, assumptions about missingness, or sensitivity analyses. Therefore, the effect of missing data on the reported arm estimates cannot be assessed from this record alone.

The registry reports arm-specific endpoint counts, but does not explain the difference between those counts and the overall enrollment figure. The analysis population details beyond the ITT description are not reported in the registry record. No protocol-specific conclusion about analysis populations, missing-data handling, interim analyses, or multiplicity should be inferred from the posted means and confidence intervals.

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: chronic obstructive pulmonary disease (3.4%), pneumonia (1.6%), squamous cell carcinoma of lung (0.7%), acute respiratory failure (0.4%), chest pain (0.4%).

The serious adverse event figures are counts of affected participants alongside the number at risk in each group. The registry reports 114 affected participants among 1036 at risk for GFF MDI, 90 among 890 for GP MDI, 78 among 890 for FF MDI, and 49 among 451 for open-label Spiriva® Handihaler®. These are group-level safety summaries; they do not state the severity, timing, duration, or outcome of every individual event.

The registry lists chronic obstructive pulmonary disease as a serious event term at 3.4%, pneumonia at 1.6%, and squamous cell carcinoma of lung at 0.7%. Acute respiratory failure, chest pain, and cellulitis are each listed at 0.4%. The record does not provide the group-specific breakdown for these terms in the information, so these percentages should not be assigned to a particular treatment group.

Deaths are not reported in the registry record. The record does not provide a detailed definition of the safety population or explain whether participants could contribute more than one event. These figures should be read as recorded safety counts, not as a comparative test of risk. No direct statistical comparison of serious adverse events is reported.

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

The primary endpoint results describe estimated changes in morning pre-dose trough FEV1, averaged across the specified follow-up visits, for each of the four groups. Each arm has a least-squares mean and a 95% confidence interval. The results give an account of estimated within-group change from baseline in the stated analysis population.

They do not report a treatment difference between GFF MDI and Spiriva® Handihaler®, or between any other pair of groups. They also do not report p-values for those contrasts. It is therefore not possible to use these arm estimates alone to establish whether one group differs from another, or how precise a difference might be. The separate confidence intervals are not a replacement for a contrast estimate and its interval.

The endpoint is one aspect of the study. The registry also names patient-reported breathlessness, peak post-dose FEV1 change, health status, and rescue medication use as secondary outcomes, but their detailed numerical results are not reported in the registry record. The record’s stated purpose includes long-term safety and tolerability, and it provides serious adverse event counts and selected event terms. Those summaries do not cover every dimension of safety or provide a formal comparative safety analysis.

More generally, a group average does not describe the distribution of individual participant responses. It should not be treated as a prediction for a particular person. The posted information also does not establish how the estimates would apply beyond this study population, which consisted of people completing one of the specified lead-in studies. No treatment recommendation follows from the registry summaries.

13. Why This Trial Matters Statistically

This study is statistically notable for its extension design and its repeated-measure endpoint. Participants entered after completing one of two lead-in studies, and the primary endpoint averages post-baseline FEV1 measurements across a long follow-up window. That setting makes the analysis population and the handling of repeated observations important to interpretation.

The registry reports model-based arm estimates with confidence intervals rather than only single-visit measurements. This communicates uncertainty around each group’s estimated change. At the same time, arm-level estimates are not sufficient to answer a comparative question. Without direct contrasts and their uncertainty, readers cannot determine from these results alone how precisely the groups differed.

The record also illustrates why enrollment and analysis counts should be read in context. It lists enrollment of 892, while endpoint arm counts are larger in some groups. The endpoint population is described as coming from the lead-in studies, but the reason for the difference in counts is not reported in the registry record. Transparent reporting of population flow and analysis populations would help readers understand the scope of each estimate.

Finally, safety summaries and efficacy outcomes answer distinct questions. Serious adverse event counts describe the number of affected participants in each arm, while the primary endpoint summarizes a modeled change in lung function. Neither alone provides a complete account of the study. The absence of reported secondary numerical results, comparative tests, and details of missing-data methods limits how far statistical interpretation can go.

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 registry record does not report direct comparisons for the primary endpoint. It provides arm-specific estimates and confidence intervals but no between-group differences, p-values, or other comparative inference. This limits conclusions about relative changes across the randomized groups.

The record does not specify the statistical model used to obtain the least-squares means, the covariates included, or the approach to within-participant correlation across repeated visits. It also does not report how missing visits or incomplete follow-up were handled, or whether sensitivity analyses were conducted. These omissions make it difficult to assess model assumptions and the robustness of the estimates.

The endpoint counts exceed the overall enrollment figure in some arms. The primary population is described as the ITT population from the lead-in studies with data for the parameter, but the relationship between the enrollment and analysis counts is not explained. Detailed participant-flow information and reasons for the arm-specific counts are not reported in the registry record.

The record names four secondary outcomes without reporting their numerical results, and it does not report a multiplicity strategy or a statistical analysis plan. It also does not report the trial’s sample-size justification, any interim analyses, or the safety definition and detailed event-level information. Deaths are not reported in the registry record. These gaps limit assessment of the full efficacy and safety findings and of the planned statistical framework.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Extension Study to Evaluate the Safety and Efficacy of PT003, PT001, and PT005 in Subjects With Moderate to Very Severe COPD, With Spiriva® Handihaler® (PINNACLE 3) — NCT01970878.
• Registry record last updated 2017-03-17; status last verified 2017-02.
• Results first posted 2017-02-06.
• 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

NCT01970878 is a completed Phase 3 randomized parallel-group active-control extension study in COPD. The registry describes a 28-week extension following PT003006 or PT003007, with an overall observation period of 52 weeks. It lists GFF MDI (PT003), GP MDI (PT001), FF MDI (PT005), and open-label Spiriva® Handihaler®.

The primary outcome is model-based average change from baseline in morning pre-dose trough FEV1 from Week 2 through Week 52, in liters, for the stated ITT population with parameter data. Arm-specific least-squares means and 95% confidence intervals are reported. Direct treatment contrasts and detailed numerical secondary results are not reported in the registry record.

The record lists serious adverse event counts by arm and selected serious event terms. It does not report deaths, the detailed statistical model, missing-data procedures, multiplicity methods, or the trial’s sample-size justification.