Longitudinal Follow up to Assess Biomarkers Predictive of Emphysema Progression in Patients With COPD (Chronic Obstructive Pulmonary Disease): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Longitudinal Follow up to Assess Biomarkers Predictive of Emphysema Progression in Patients With COPD (Chronic Obstructive Pulmonary Disease) (NCT02719184), a registered phase not stated study. The primary outcome is Absolute Change From Baseline at Week 156 in Adjusted Lung Density (ALD) Based on Percentile Density at 15% (PD15) Adjusted for Lung Volume.

2. Clinical Question

The study’s stated aim is to assess relationships among clinical measurements, imaging, biomarkers, and emphysema progression over three years. This question is descriptive and associational in the context of an observational design. It does not, by itself, establish that a biomarker causes progression or that a group difference is due to COPD severity. The record identifies six outcome measures and eight analyses, but does not report the biomarker-specific findings or the numerical primary endpoint result.

3. Trial Design

This completed study is an observational follow-up of healthy subjects and people with COPD. The registry title describes an assessment of clinical, imaging, and biomarker measurements in relation to emphysema progression over three years. There is no randomized treatment assignment in the record, and allocation is not stated. The listed groups should therefore be understood as cohort categories rather than treatment and control arms.

The brief summary describes planned enrollment of 60 healthy subjects, 125 participants with COPD GOLD I, 125 with COPD GOLD II, 125 with COPD GOLD III, and up to 20 patients with COPD and A1AT deficiency. Overall enrollment is reported as 463. Each group description gives an observational period of 156 weeks. The listed planned group counts and overall enrollment describe different aspects of the record; the record does not explain any difference between planned group targets and the enrolled total.

The study started on 2016-04-13, had a primary completion date of 2021-06-14, and is marked COMPLETED. The primary endpoint is change from baseline at Week 156 in adjusted lung density, a continuous outcome measured in gram/Liter (g/L). The endpoint description states that the analysis used a Mixed Model for Repeated Measures (MMRM). The primary analysis population was a per-protocol biomarker population, restricted to participants without specified important protocol deviations affecting clinical or biomarker assessments and with non-missing results.

The record lists six outcome measures and eight analyses. It does not report the full statistical analysis plan, detailed measurement schedules, a randomized comparator, or numerical primary results. Accordingly, the design supports description of measurements and their relationships across the observed groups; it does not support interpreting group contrasts as randomized treatment effects.

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: All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per-Protocol Set (Biomarker Subjects): All subjects, from the Observed subjects set, who have no Important Protocol Deviations (IPDs) affecting the clinical or biomarker assessments. Only participants with non-missing results were included in the analysis.

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: Observed subjects set (OBS): All subjects, from the Screened subjects set (SCR), who are eligible to enter the observation period.

6. Primary Endpoint

The registry lists the primary outcome as Absolute Change From Baseline at Week 156 in Adjusted Lung Density (ALD) Based on Percentile Density at 15% (PD15) Adjusted for Lung Volume, measured over Up to Week 156. Change from baseline value at Week 156 was reported..

The primary endpoint is the absolute change from baseline at Week 156 in adjusted lung density, measured in gram/Liter (g/L). The record defines adjusted lung density (ALD) using the 15th percentile density measure (PD15) and a lung-volume adjustment: PD15 is multiplied by inspiratory volume divided by predicted total lung volume. The endpoint is therefore not simply the unadjusted density value; it incorporates a volume adjustment as specified in the registry description.

The endpoint is continuous. Its stated summary is a least-squares mean, with standard error as the measure of dispersion. A mean change describes the average model-estimated change for the analyzed population, while a standard error describes uncertainty in that estimated mean. The numerical estimate and standard error are not reported in the registry record, so the size, direction, and precision of the primary result cannot be assessed from the available record.

As a general measurement principle, using a defined quantitative imaging endpoint can make changes over follow-up expressible on a continuous scale rather than only as categories. The registry identifies adjusted lung density as the primary measure for assessing emphysema progression in this study. The volume adjustment is part of the endpoint’s definition; its inclusion should not be taken as evidence that other sources of measurement or modeling uncertainty have been removed.

The endpoint is described as a change from baseline at Week 156, with the analysis using repeated-measures modeling. No numerical estimate, standard error, confidence interval, or group-specific primary result is reported in the registry record. The clinical interpretation must therefore remain limited to what was planned and measured, rather than a conclusion about the direction or magnitude of change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary analysis is described as a Mixed Model for Repeated Measures (MMRM) applied to absolute change from baseline in adjusted lung density. The outcome is continuous, and the registry reports the model-based result as a least-squares mean with a standard error. The record gives this broad method description, but the full model specification and numerical output are not reported in the registry record.

What a repeated-measures model does

General statistical explanation: when participants have measurements at multiple follow-up times, those measurements from the same participant are usually related rather than independent. A repeated-measures model is designed to analyze such longitudinal observations while accounting for within-participant correlation. It can use the pattern of repeated measurements to estimate change over time, rather than treating every observation as if it came from a different participant.

MMRM is a modeling approach, not a guarantee that every participant completed every visit or that missing measurements have no effect on the result. The registry says the endpoint is change from baseline at Week 156 and identifies MMRM as the analysis method. It does not report the covariance structure, the fixed effects, any covariates, or the model’s assumptions about missing observations. Those details matter when assessing how a model-based estimate was obtained and how robust it may be.

What the least-squares mean and standard error convey

General statistical explanation: a least-squares mean is an estimated mean from a statistical model. It can differ from a raw average because the model may account for other terms or the structure of the data. The standard error describes the sampling uncertainty of the estimated mean under the model; it is not the spread of individual participants’ measurements. A smaller standard error generally indicates a more precise estimate, but it cannot be interpreted without the estimate and other relevant information.

The registry describes the primary endpoint as a least-squares mean and reports standard error as its dispersion measure. It does not include a numerical estimate or standard error in the record summarized by these results. Consequently, the precision of the primary endpoint cannot be evaluated, and no confidence interval or test result can be inferred. A standard error alone, even if it were available, would not describe the range of individual changes.

Why the endpoint includes a volume adjustment

The registry defines adjusted lung density using PD15 multiplied by inspiratory volume divided by predicted total lung volume. This formula makes the lung-volume adjustment part of the endpoint itself. The primary endpoint then evaluates change from baseline in that adjusted measure. General statistical explanation: defining an outcome with an adjustment can make the target measurement account for a specified feature of how it is measured. It does not remove all possible measurement error or establish that the adjusted measure captures every aspect of disease progression.

The record does not report the component measurements or numerical values used to calculate the primary outcome. It also does not report enough detail to independently assess the calculation or the effects of any measurement variability. The formula should therefore be read as the registry’s definition of the endpoint, not as an independent validation of the measure.

How to interpret a confidence interval and a p-value

General statistical explanation: a confidence interval expresses a range of values compatible with the data and the statistical model at a stated confidence level. Its width conveys information about precision, while its position conveys information about the estimated effect. A p-value measures how unusual the observed data, or data more extreme, would be under a specified null model. Neither measure communicates clinical importance on its own, and neither replaces examination of the estimated effect and the analysis assumptions.

The registry record does not report a primary confidence interval or p-value. It is therefore not possible to characterize the primary finding as statistically significant or not, or to assess the range of values compatible with the result. No significance threshold or complete inferential plan for the primary analysis is reported in the registry record.

Observational comparisons and confounding

General statistical explanation: in an observational study, participants are not assigned at random to the groups being compared. Group membership may be associated with other participant characteristics that also relate to the outcome. Such factors can confound a group comparison, making it difficult to attribute a difference to group membership itself. Adjustment in a model can address measured factors if they are specified and appropriately modeled, but cannot automatically address unmeasured differences.

This study lists healthy subjects and COPD categories, including a group with A1AT deficiency. The registry does not identify randomized arms or a like-for-like control comparison. It does not report a complete adjustment strategy for potential confounders. Accordingly, descriptive group patterns, if available, should not be interpreted as causal effects of COPD category or treatment.

Planning illustrations are not observed power

The record describes planning illustrations based on an observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. For non-time-to-event outcomes, the stated planning quantities are participants per arm. These are planning assumptions, not trial outcomes or evidence of the probability that the study detected an effect. They must not be described as observed power.

The study is observational, and the record does not describe a randomized two-arm design. The illustrations therefore do not turn the cohort groups into randomized arms or establish a causal comparison. No actual numerical planning illustration or observed primary effect is reported in the registry record. Without those values, no planning quantity can be interpreted numerically.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Healthy Subjects", "COPD GOLD I", "COPD GOLD II", "COPD GOLD III", "COPD and A1AT Deficiency")
n   <- c(41, 64, 51, 37, 5)
m   <- c(-0.27, -3.15, -5.04, -4.74, -6.13)
sp  <- c(1, 0.79, 0.84, 1.04, 2.51)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Healthy Subjects  41  -0.270  6.403  -2.291  1.751
CARM  COPD GOLD I  64  -3.150  6.320  -4.729  -1.571
CARM  COPD GOLD II  51  -5.040  5.999  -6.727  -3.353
CARM  COPD GOLD III  37  -4.740  6.326  -6.849  -2.631
CARM  COPD and A1AT Deficiency  5  -6.130  5.613  -13.099  0.839

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and eight analyses. It identifies the change in adjusted lung density at Week 156 as the primary endpoint, but does not report a full statistical analysis plan or a multiplicity strategy. In a study with several outcomes or analyses, repeated testing can increase the chance of finding an apparently notable result by chance. General statistical explanation: multiplicity methods can control or describe that issue, but the appropriate approach depends on the questions and analysis plan.

Because no numerical results or adjustment method are reported in the registry record, it is not possible to assess whether inferences across outcomes were adjusted, whether analyses were prespecified, or how much weight to place on any secondary finding. The number of outcomes and analyses alone does not establish that a multiplicity problem occurred; it indicates why the planned hierarchy and inferential approach would be useful to know.

For the primary endpoint, the analysis population is described as the Per-Protocol Set (Biomarker Subjects). It includes participants from the Observed subjects set who had no Important Protocol Deviations affecting clinical or biomarker assessments and who had non-missing results. This restriction defines who contributed to the reported primary analysis as described in the registry. The record does not report the number excluded for protocol deviations, the number with missing endpoint data, or how those exclusions affected the estimate.

The analysis method is MMRM, but detailed missing-data assumptions and sensitivity analyses are not reported in the registry record. General statistical explanation: repeated-measures models can use available observations under assumptions about the missing-data process; they do not, by themselves, prove that missingness is harmless. Without the missingness counts, reasons, assumptions, and sensitivity analyses, the potential influence of incomplete follow-up cannot be evaluated.

Interim analyses, stopping rules, and further details about the statistical plan are not reported in the registry record. No assumptions about them can be made from the endpoint description alone.

12. 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 5% reporting threshold.

The registry reports serious adverse event and other adverse event counts separately for each group. In the healthy subjects group, 0 participants were affected by serious adverse events and 0 by other adverse events; deaths were 0. In COPD GOLD I, the corresponding figures were 0, 0, and 0. In COPD GOLD II, they were 0, 0, and 0; in COPD GOLD III, 0, 0, and 0; and in COPD and A1AT deficiency, 0, 0, and 0.

The listed numbers at risk were 62 healthy subjects, 123 participants with COPD GOLD I, 130 with COPD GOLD II, 129 with COPD GOLD III, and 19 with COPD and A1AT deficiency. These are the group-specific denominators reported for the adverse-event figures. The registry record does not report serious adverse event terms, and no top serious event terms are listed.

These counts describe what the registry records for the listed groups. Zero recorded events is not, by itself, evidence that no events occurred outside the reported ascertainment or follow-up. Definitions, event-collection procedures, and details about the completeness of safety follow-up are not reported in the registry record. Because the study is observational, these figures also should not be read as a comparison of safety between randomized treatments.

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

The record establishes that this was a completed observational study with planned follow-up over 156 weeks and a primary endpoint focused on change in adjusted lung density at Week 156. It describes five participant categories, the endpoint formula, the analysis population, and use of MMRM. It does not report the numerical primary estimate, standard error, confidence interval, or p-value. The direction, magnitude, and precision of the primary result therefore cannot be stated.

The study aim concerns relationships among clinical measurements, imaging, soluble biomarkers, and emphysema progression. A stated aim is not a finding. The registry record does not report the particular biomarker associations or whether any biomarker was predictive of progression. It also does not provide evidence that an observed association, if one was found, was causal. Prediction, association, and causation are different statistical questions and require different evidence.

The presence of healthy and COPD groups permits description of measurements across those groups, but does not create a randomized control comparison. Allocation is not stated, and the record does not establish that groups were comparable apart from their listed category. Any differences across observed groups could reflect other characteristics or measurement factors. They should not be interpreted as effects caused by being in a particular group.

The adverse-event figures record zero affected participants for serious events and zero for other events in every listed group, with zero deaths in every group. These counts should be understood within the registry’s reported populations and event reporting. They do not establish that risk is absent or allow a causal safety comparison.

More generally, a model-based estimate needs to be read alongside its uncertainty, analysis population, assumptions, missing-data handling, and the study design. Those details are not fully reported for this study. The registry information supports a description of what the study set out to measure and how its primary endpoint was analyzed, but not a numerical conclusion about the endpoint or a claim about treatment efficacy.

14. Why This Trial Matters Statistically

This study illustrates a common statistical challenge in longitudinal biomarker research: the scientific question concerns change over time, while measurements may be repeated within the same participant and may be incomplete. The registry identifies MMRM for its primary endpoint, a method intended to analyze repeated outcome measurements while accounting for their within-participant structure. Interpreting the result still requires the model details, uncertainty estimates, and information about missing follow-up.

It also demonstrates why endpoint definitions matter. Adjusted lung density is defined using PD15 and a lung-volume adjustment, and the primary outcome is change from baseline at Week 156. Readers need to distinguish this specific derived measure from an unadjusted imaging value or from a general claim about emphysema. The registry’s formula clarifies what was targeted, but the numerical result and measurement details are not reported.

The observational design is equally important to interpretation. Healthy participants and several COPD groups can provide a framework for examining patterns and relationships, but the group labels do not imply randomized assignment. The study can address associations among measured characteristics in its observed participants; the design alone cannot establish that differences are caused by group membership or a treatment.

Finally, the record lists multiple outcome measures and analyses without reporting a multiplicity approach or the numerical results. This makes transparent reporting of prespecified questions, analysis choices, missingness, and uncertainty especially important. In this case, the registry communicates the study structure and primary method, but does not provide enough outcome detail to judge the evidence for biomarker relationships or the size and precision of the primary change.

15. 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 central limitation for statistical interpretation is that the registry record does not report the numerical primary endpoint result. The estimate, standard error, confidence interval, and p-value are unavailable, so the direction, magnitude, and precision of change in adjusted lung density cannot be evaluated. Numerical results for biomarker relationships are also not reported.

The study is observational, and allocation is not stated. The healthy and COPD categories are not randomized treatment arms or a like-for-like control comparison. Comparisons across these groups may be affected by differences beyond the group labels. The record does not report a complete strategy for adjustment for potential confounders, so causal interpretations are not supported by the design information available.

The MMRM description does not include model specification details such as covariates, covariance structure, or detailed assumptions. The primary population excludes participants with specified important protocol deviations and requires non-missing results. Counts of exclusions and missing outcomes, reasons for missingness, and sensitivity analyses are not reported in the registry record. The influence of these choices and any incomplete follow-up cannot be assessed.

The registry lists six outcome measures and eight analyses but does not report the multiplicity strategy, full analysis plan, or which analyses were prespecified. Interim analyses and stopping rules are not reported. The endpoint formula is given, but measurement reliability and component-level results are not reported. The study’s stated biomarker aim therefore cannot be judged from the aim alone.

Safety figures report zero affected participants for serious and other adverse events and zero deaths in each group. The event definitions, ascertainment process, and completeness of safety reporting are not described. These limitations restrict interpretation of both the primary endpoint and the broader biomarker and safety questions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Longitudinal Follow up to Assess Biomarkers Predictive of Emphysema Progression in Patients With COPD (Chronic Obstructive Pulmonary Disease) — NCT02719184.
• Registry record last updated 2024-08-16; status last verified 2024-03.
• Results first posted 2024-08-16.
• 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.

19. Record Summary

NCT02719184 is a completed observational study titled “Longitudinal Follow up to Assess Biomarkers Predictive of Emphysema Progression in Patients With COPD.” Its official title describes assessment of clinical, imaging, and biomarker measurements in healthy subjects and patients with COPD over three years. The study lists overall enrollment of 463, with healthy subjects, COPD GOLD I, COPD GOLD II, COPD GOLD III, and COPD with A1AT deficiency groups. Each group description gives an observational period of 156 weeks.

The primary endpoint is absolute change from baseline at Week 156 in adjusted lung density based on PD15 and adjusted for lung volume. The analysis population is the Per-Protocol Set (Biomarker Subjects), and the analysis method is MMRM. The record lists six outcome measures and eight analyses. Numerical primary results, detailed model specifications, biomarker findings, and a full multiplicity and missing-data plan are not reported in the registry record. Serious and other adverse event counts and deaths are recorded as 0 in every listed group.