Effect of Symbicort ® on GR in Sputum in COPD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Symbicort ® on GR in Sputum in COPD (NCT01787097), a randomized phase 4 study. The primary outcome is GR-GRE Binding (Relative to Baseline).

2. Clinical Question

3. Trial Design

The registry record describes a completed phase 4, randomized, unmasked crossover trial sponsored by Imperial College London. Enrollment was 31. The recorded start was 2013-01, and primary completion was 2014-12. The record lists COPD as the condition under study.

A crossover design means participants receive more than one treatment over the course of the study, so comparisons can potentially use information from the same person under different treatments. The registry record identifies the design as crossover, but does not report the treatment sequence, the timing or duration of treatment periods, any washout period, or the method used to account for within-participant correlation. Those details are not reported in the registry record.

The listed treatments were Formoterol 24ug, Symbicort® at total doses of 400ug/12ug and 800ug/24ug, and Pulmicort 800ug. The record describes the two Symbicort® regimens as combinations of formoterol and budesonide, with the 800ug/24ug regimen identified as the higher dose. Pulmicort is described as an intermediate dose of inhaled corticosteroid. The registry record does not report the treatment sequence or explain whether every participant received every listed treatment.

Although the trial enrolled 31 participants, the primary outcome summaries include smaller group counts: 5 for Formoterol, 6 for each Symbicort® dose, and 7 for Pulmicort. The record attributes low patient numbers for the primary outcome to the difficulty of producing sputum of adequate quality and to variability in sputum production between visits. It does not report a participant flow accounting for the differences in group counts.

The registry record does not report a protocol-based sample-size justification, a prespecified interim analysis, or detailed analysis-population definitions. It also does not report the planned statistical analysis for the secondary outcomes.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Low patient numbers due to the fact that only a small number of patients were able to produce sputum that was of sufficient quality to undertake analysis, furthermore, sputum production between patient visits was highly variable.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as GR-GRE Binding (Relative to Baseline), measured over Screening visit and 2 hours post inhalation of treatment.

The primary endpoint was glucocorticoid receptor–glucocorticoid response element (GR-GRE) binding, expressed as fold activation relative to baseline. The registry record describes measurement using an enzyme immunosorbent assay system in induced sputum macrophages. Measurements were taken at screening and two hours after inhalation of treatment.

This is a biological, continuous outcome. It captures a laboratory measure of receptor-related activity in airway cells rather than a symptom, exacerbation, or other clinical outcome. Studying sputum allows investigators to examine cells collected from the airways, which the record identifies as the site of disease. As a general statistical point, such a biomarker can help characterize a biological response, but a difference in the biomarker does not by itself establish the size or importance of a change in patients’ clinical health.

The posted summaries report means and standard errors for the treatment groups. For the primary outcome, those means were 1.1 for Formoterol 24ug, 1.8 for Symbicort® 400ug/12ug, 2.3 for Symbicort® 800ug/24ug, and 2.1 for Pulmicort 800ug. The reported group counts were 5, 6, 6, and 7, respectively. The registry-reported inferential analysis was a Wilcoxon (Mann-Whitney) comparison between the two Symbicort® groups, with p = 0.003. The registry record does not report a confidence interval or an estimated difference for that analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Continuous outcomes are measurements that can take a range of values, such as fold activation or cytokine concentration. The registry record reports group means and standard errors. A mean describes the average observed value in a group. A standard error describes the uncertainty in that estimated mean, rather than the spread of individual participant measurements. It is therefore not interchangeable with a standard deviation.

What does the primary test assess?

The registry-reported primary analysis used a Wilcoxon (Mann-Whitney) test to compare the two Symbicort® groups. As a general statistical explanation, this rank-based test compares the distributions of observations between groups by ordering the observed values. It does not directly estimate a difference between group means. A small p-value indicates that the observed rank pattern would be unusual under the test’s null hypothesis, subject to the assumptions and analysis actually used. It does not measure the probability that the null hypothesis is true, nor does it quantify clinical importance.

The registry record reports p = 0.003 for this comparison, but does not report the test statistic, an effect estimate, or a confidence interval. Without an estimated difference and interval, the magnitude and precision of the primary contrast cannot be assessed from the registry-reported analysis. The posted group means provide descriptive context, but they do not replace an effect estimate from the reported test.

How should confidence intervals and recalculations be read?

A confidence interval is a range of values compatible with the data and the method used to construct it. In general, a wider interval indicates less precision, while an interval that includes the no-difference value does not provide clear evidence of a difference at the corresponding confidence level. The secondary comparisons include recalculated mean differences and confidence intervals. These are simple, unadjusted calculations from posted summary statistics, not registry-reported analyses. They do not account for any analysis features that cannot be recovered from the summaries, including possible pairing in the crossover design.

The secondary recalculations compare each Symbicort® dose with Formoterol 24ug. Their mean differences are expressed with the Symbicort® group as the compared treatment and Formoterol as the reference. The confidence intervals communicate uncertainty in those unadjusted estimates. The corresponding p-values are also unadjusted. They should not be confused with the primary Wilcoxon result, which is a registry-reported test comparing the two Symbicort® groups.

Why does crossover structure matter?

In a crossover study, observations from the same participant under different treatments may be correlated. As a general statistical principle, a paired analysis can use that within-person relationship and may have different precision from an analysis that treats groups as independent. Appropriate analysis may also need to consider treatment sequence or period effects, depending on the design. The registry record identifies a crossover model but does not report the sequence, period structure, washout arrangements, or whether the primary or secondary analyses accounted for pairing. The summary-statistic recalculations therefore cannot be assumed to reproduce a crossover-aware analysis.

The posted group counts also differ across endpoints. For example, primary outcome counts are lower than the enrollment total, and secondary outcome counts vary by treatment and measure. As a general matter, analyses based on different subsets of participants can differ because of both treatment response and who contributed data. The registry record notes sputum availability and variability as reasons for the low primary outcome numbers, but does not describe a missing-data method or establish that data were missing at random.

What do the planning illustrations mean?

The sample-size illustrations use observed secondary-outcome effects as planning inputs. They apply the stated assumptions: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The rows illustrate planning for 100%, 75%, or 50% of the observed effect. They report participants per arm for 80% power and participants per arm for 90% power.

These values are hypothetical planning illustrations, not the trial’s enrollment target, not observed power, and not evidence that a future study would obtain the observed effect. They depend on the effect and variability estimates from the current small samples, which may be unstable. The registry record does not report the trial’s own sample-size justification, so the illustrations cannot be used to infer how the original study was designed.

The calculations for secondary outcomes are unadjusted, and the registry record does not report whether multiplicity was addressed in the original analysis. General statistical practice treats multiple comparisons cautiously because testing many outcomes or contrasts can increase the chance of finding an apparently notable result by chance. The posted unadjusted p-values do not account for that issue.

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("Formoterol (FORM) Total Dose 24ug", "Symbicort® Total Dose 400ug/12ug", "Symbicort® Total Dose 800ug/24ug", "Pulmicort 800ug")
n   <- c(5, 6, 6, 7)
m   <- c(1.1, 1.8, 2.3, 2.1)
sp  <- c(0.1, 0.1, 0.4, 0.2)
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  Formoterol (FORM) Total Dose 24ug  5  1.100  0.224  0.822  1.378
CARM  Symbicort® Total Dose 400ug/12ug  6  1.800  0.245  1.543  2.057
CARM  Symbicort® Total Dose 800ug/24ug  6  2.300  0.980  1.272  3.328
CARM  Pulmicort 800ug  7  2.100  0.529  1.611  2.589

11. Analyses Reported by the Sponsor

The registry-reported primary analysis and the summary-statistic recalculations address different information. The sponsor’s recorded analysis is a Wilcoxon (Mann-Whitney) comparison between Symbicort® 400ug/12ug and Symbicort® 800ug/24ug, with p = 0.003. It is a rank-based test, while the posted primary summaries are means and standard errors. The registry record does not report an effect estimate or confidence interval for the sponsor’s primary test.

No recalculated primary comparison is reported. The simple recalculations available for the secondary outcomes use means, standard errors, and group counts to estimate unadjusted mean differences and confidence intervals. They compare each Symbicort® dose with Formoterol, rather than comparing the two Symbicort® doses. They are not a substitute for the sponsor’s primary analysis and do not validate or contradict its result.

The sponsor’s own analysis takes precedence for the primary endpoint because it is the analysis reported for that endpoint in the registry record. The registry record does not provide enough detail to determine whether it incorporated the crossover structure, how missing primary outcome data were handled, or whether the analysis followed a prespecified plan. Those uncertainties affect interpretation, but do not justify replacing the reported primary test with a different calculation.

12. Multiplicity, Missing Data and Analysis Populations

The registry record identifies one primary outcome and lists secondary outcomes for IL-6, CXCL8, TNF Alpha, and FEV1. It reports a primary Wilcoxon (Mann-Whitney) test comparing the Symbicort® dose groups. It does not report a prespecified hierarchy among outcomes, a multiplicity adjustment, or a plan distinguishing confirmatory from exploratory analyses. The secondary recalculated p-values are unadjusted.

As a general statistical matter, evaluating multiple outcomes or treatment contrasts increases the chance that at least one result will look unusual even when no underlying difference exists. Adjustment methods or a prespecified testing hierarchy can address this concern, but the registry record does not report that either was used. Consequently, individual unadjusted secondary p-values should not be treated as if they arose from a single isolated test. The record also does not report whether there were additional analyses beyond the posted results.

Missing outcome data are relevant because the primary endpoint summaries include fewer participants than the enrollment total. The registry record says that few patients could produce sputum of sufficient quality and that sputum production varied between visits. It does not report the number of participants with missing observations for each visit, reasons for missingness by treatment, an imputation method, or a sensitivity analysis. The extent to which missingness could have influenced the reported estimates cannot therefore be assessed from the record.

The record does not report detailed analysis-population definitions, such as whether participants were analyzed according to randomized treatment, treatment received, or availability of an evaluable sample. It also does not report how crossover pairing, treatment sequence, or period effects were handled. These omissions matter because both the analysis population and the handling of within-participant observations can affect estimates and their uncertainty. The registry record does not report a protocol-based sample-size justification or an interim-analysis plan either. These details should not be inferred from the posted results.

13. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The adverse-event figures list 31 participants at risk in each of the four treatment groups. For each listed treatment, the registry record reports zero serious adverse events, zero other adverse events, and zero deaths. No serious adverse-event terms are listed.

These figures describe what was posted in the registry record; they should not be read as proof that no adverse events occurred in any broader sense. The record does not provide additional detail about how adverse events were collected, their timing, their severity beyond the serious-event classification, or how events were attributed to treatment. It also does not explain how the at-risk counts relate to treatment periods in this crossover design. The absence of reported events in these fields is therefore a limited description of the posted safety data, not a comprehensive safety assessment.

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

The primary finding is a reported statistical difference between the two Symbicort® dose groups on the GR-GRE binding outcome. The registry reports p = 0.003 from a Wilcoxon (Mann-Whitney) test. The group means are descriptive, and the registry record does not report an effect estimate or confidence interval for that test. The result therefore indicates evidence of a difference under the reported test, but the size and precision of the contrast are not fully characterized in the record.

The endpoint is a laboratory measure in induced sputum macrophages. A biomarker difference can inform understanding of biological activity, but it does not by itself establish a meaningful change in symptoms, lung function, exacerbations, or other patient-important outcomes. The record lists changes in FEV1 as a secondary outcome, but does not report a result for it. The posted primary result should not be extended to clinical outcomes that are not reported.

The secondary comparisons are exploratory in interpretation: they are unadjusted recalculations, use contrasts with Formoterol rather than the primary dose-to-dose contrast, and arise across several outcomes. Their pattern is not uniform. The registry record does not report a multiplicity strategy, so isolated secondary findings deserve caution.

The primary outcome group counts are small, and the registry record describes limitations in obtaining sputum samples of sufficient quality. The record does not provide enough detail about missing-data handling or crossover-aware analysis to resolve how these features affected precision. The study results should therefore be understood as evidence about the posted biomarker measurements and comparisons, not as a complete account of treatment effects across clinical outcomes or all participants.

15. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the distinction between a biological endpoint and a clinical endpoint. GR-GRE binding in sputum macrophages addresses a mechanistic question about activity in airway cells. The registry record’s stated purpose was to investigate how combination treatment may relate to inflammatory processes in COPD. A biomarker can be relevant to such a question while still leaving clinical benefit, harm, and patient experience unresolved.

The record also shows why outcome availability is central to interpretation. Enrollment was 31, while the primary summaries include smaller group counts. The stated difficulty producing adequate sputum and variability between visits help explain why the available outcome data are limited. In a small dataset, a statistically notable test result can coexist with uncertainty about the magnitude, representativeness, and reproducibility of the estimated effect.

The crossover design adds another statistical consideration. Within-participant comparisons can be useful, but their interpretation depends on design details and analysis methods, including handling of repeated observations. The registry record identifies the crossover model without reporting the sequence or analysis of within-person correlation. That gap makes it difficult to determine how well the reported methods reflect the design.

Finally, the primary and secondary analyses answer different questions. The registry-reported primary test compares the Symbicort® doses, while the secondary recalculations compare each dose with Formoterol. Keeping those contrasts separate prevents a result for one question from being mistaken for evidence about another. The case underscores the value of complete reporting of effect estimates, uncertainty, missing-data procedures, multiplicity plans, and analysis methods.

16. 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 primary endpoint was available for only a small number of participants in each treatment group, and the record attributes this to sputum sample quality and variable sputum production between visits. It does not provide a detailed account of missing observations by visit or treatment, so the impact of incomplete outcome data cannot be assessed.

The registry reports a p-value for the primary Wilcoxon comparison but no effect estimate, confidence interval, test statistic, or detailed description of the analysis population. It also does not report whether the analysis accounted for the crossover structure, including within-participant correlation, treatment sequence, or period effects. The treatment order and any washout period are not reported in the registry record.

The secondary mean-difference calculations are unadjusted and based on posted summary statistics. They do not reproduce a crossover-aware analysis, and the record does not report original inferential analyses for those outcomes. The registry also does not report a multiplicity plan. FEV1 is listed among the secondary outcomes, but a result is not reported in the registry record.

There is no reported protocol-based sample-size justification, interim-analysis plan, or complete explanation of analysis populations. The planning illustrations use observed effects and stated assumptions; they cannot establish the adequacy of the original trial’s design. Finally, the primary endpoint is a biomarker, so the registry-reported result alone does not establish effects on clinical outcomes.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Effect of Symbicort ® on GR in Sputum in COPD — NCT01787097.
• Registry record last updated 2020-11-23; status last verified 2020-10.
• Results first posted 2020-11-23.
• 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.

20. Record Summary

The registry record describes a completed, randomized, unmasked, phase 4 crossover trial sponsored by Imperial College London, with 31 enrolled participants and COPD as the condition under study. The primary outcome was GR-GRE binding in induced sputum macrophages, expressed as fold activation relative to baseline and measured two hours after inhalation.

The primary summaries include small treatment-group counts, and the registry reports a Wilcoxon (Mann-Whitney) comparison between the two Symbicort® doses with p = 0.003. The registry record does not report an effect estimate or confidence interval for that primary analysis. Secondary outcomes include inflammatory biomarkers and FEV1; available recalculations are unadjusted, and a result for FEV1 is not reported in the registry record.

The record reports zero serious adverse events, zero other adverse events, and zero deaths for each listed treatment group. Missing-data procedures, crossover-analysis details, and a multiplicity plan are not reported in the registry record.