Efficacy, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide and Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide and Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) (NCT01437397), a randomized phase 3 study. The primary outcome is Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1).

2. Clinical Question

3. Trial Design

This was a Phase III, randomized, parallel-group study with quadruple masking and placebo control. The registry record lists an enrollment of 1692. The study evaluated five arms: aclidinium/formoterol 400/12 μg, aclidinium/formoterol 400/6 μg, aclidinium 400 μg, formoterol 12 μg, and placebo. The official title describes a 24-week treatment period, and the brief summary says treatment followed a run-in period and was followed by a two-week follow-up visit. The duration of the run-in period is not reported in the registry record.

The registry lists the study as completed. The recorded start is 2011-09 and primary completion is 2013-02; the sponsor is AstraZeneca. The design description identifies randomization and masking but does not report the allocation procedure, the masking procedures for each role, or the specific randomization ratio. Those details are not reported in the registry record.

The primary outcome was change from baseline in one-hour morning post-dose FEV1 at Week 24. The primary analysis population is defined as randomized patients who received at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment. This is a specified analysis population, not necessarily every person enrolled or randomized. The registry record does not give arm-specific counts for exclusions from this population or details of the handling of missing outcome observations.

The secondary outcomes listed are change in Transition Dyspnea Index (TDI) Focal Score and change from baseline in St George's Respiratory Questionnaire (SGRQ) Total Score, both at Week 24. The record includes sponsor-reported mixed-model analyses for selected comparisons, but a complete statistical analysis plan and the original sample-size justification are not reported in the registry record.

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: A total of 3260 patients were screened for eligibility; 1692 patients were randomized to treatment. A total of 1568 (48.1%) patients screen failed and were discontinued prior to randomization. The primary reason for screening failures was not meeting inclusion/exclusion criteria (41.6%)

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT Population defined as all randomized patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

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: Safety population comprising all patients randomized to a treatment group who received at least 1 dose of double-blind investigational treatment.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1), measured over Week 24 of treatment.

The primary endpoint is the change from baseline in one-hour morning post-dose forced expiratory volume in one second (FEV1), measured in liters at Week 24 of treatment. FEV1 records how much air a person can forcibly exhale in the first second of a breathing test. It is a continuous measure of airflow and is used in COPD trials to assess lung function and the effect of maintenance bronchodilator treatment.

Change from baseline focuses on movement over the treatment period rather than the Week 24 measurement alone. In the posted results, each arm is represented by a least-squares mean change and a standard error. A positive change indicates an increase from baseline on this scale; the placebo arm's posted mean change is negative. Comparisons between arms summarize differences in their estimated mean changes.

The primary outcome is specifically a morning measurement taken one hour after dosing. It therefore describes the outcome at that stated time and under that measurement condition; it does not by itself describe lung function at every time of day, the full course of symptoms, or long-term outcomes. The registry record reports the endpoint at Week 24, and does not state a threshold for interpreting a particular FEV1 difference as clinically important. That threshold is not reported in the registry record.

The ITT Population definition requires at least one post-baseline FEV1 assessment as well as baseline data and study medication exposure. The resulting endpoint analysis describes that defined population, rather than necessarily every enrolled patient.

7. Results Posted in the Registry

• Aclidinium/Formoterol 400/12 μg: mean 0.25 versus -0.04 on control; difference 0.28 (95% CI 0.25 to 0.32), standardized effect d = 1.15; z-test p = <0.001.
• Aclidinium/Formoterol 400/6 μg: mean 0.23 versus -0.04 on control; difference 0.26 (95% CI 0.23 to 0.30), standardized effect d = 1.07; z-test p = <0.001.
• Aclidinium 400 μg: mean 0.14 versus -0.04 on control; difference 0.18 (95% CI 0.14 to 0.21), standardized effect d = 0.71; z-test p = <0.001.
• Formoterol 12 μg: mean 0.17 versus -0.04 on control; difference 0.20 (95% CI 0.16 to 0.24), standardized effect d = 0.82; z-test p = <0.001.

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.

Change in Transition Dyspnea Index (TDI) Focal Score

• 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 errors.
• Result:
  • Aclidinium/Formoterol 400/12 μg: mean 2.02 versus 0.58 on control; difference 1.44 (95% CI 0.85 to 2.02), standardized effect d = 0.38; z-test p = <0.001.
  • Aclidinium/Formoterol 400/6 μg: mean 1.98 versus 0.58 on control; difference 1.40 (95% CI 0.82 to 1.97), standardized effect d = 0.37; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Aclidinium/Formoterol 400/12 μg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Aclidinium/Formoterol 400/6 μg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score

• 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 errors.
• Result:
  • Aclidinium/Formoterol 400/12 μg: mean -6.57 versus -2.21 on control; difference -4.35 (95% CI -6.46 to -2.25), standardized effect d = -0.31; z-test p = <0.001.
  • Aclidinium/Formoterol 400/6 μg: mean -5.94 versus -2.21 on control; difference -3.73 (95% CI -5.82 to -1.64), standardized effect d = -0.27; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Aclidinium/Formoterol 400/12 μg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Aclidinium/Formoterol 400/6 μg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary outcomes cover dyspnea, measured with the TDI Focal Score, and respiratory health status, measured with the SGRQ Total Score. Across the two combination arms, the reported mean changes are in a direction that separates them from placebo on both measures: TDI changes are higher, while SGRQ changes are more negative. This general pattern is compatible with the direction of the primary FEV1 comparisons, while reflecting different patient-reported domains rather than lung function itself.

The registry includes sponsor-reported mixed-model comparisons of each combination with placebo for these secondary outcomes. The posted results also include simple unadjusted re-calculations. These measures should be treated as complementary evidence, not as interchangeable endpoints: dyspnea, health status, and FEV1 capture different aspects of COPD and have different scales and variability.

Secondary results generally carry less inferential weight than a prespecified primary endpoint, particularly when many outcomes or comparisons are examined. Testing multiple hypotheses raises the chance of at least one apparently notable result by chance unless an appropriate multiplicity strategy is used. Whether the secondary analyses were prespecified in detail, how multiplicity was handled, and whether the reported p-values were adjusted are not reported in the registry record. Accordingly, statistical significance in an individual secondary comparison should not be treated as equivalent to confirmation of a primary trial conclusion. No threshold for a clinically important change in either secondary measure is reported in the registry record.

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

• Change in Transition Dyspnea Index (TDI) Focal Score
• Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score

9. Statistical Interpretation

10. Statistical Methods Explained

What does a least-squares mean represent?

General: A least-squares mean is an estimate from a statistical model. It can account for the model terms included in that analysis, rather than being simply the raw average of observed values. The registry reports least-squares mean changes for the primary outcome and identifies mixed models for selected sponsor-reported comparisons. The full model specification, including all covariates and assumptions, is not reported in the registry record.

For the primary outcome, the arm-level least-squares mean changes are reported with standard errors. A standard error describes the estimated sampling uncertainty of a mean estimate; it is not the spread of individual patients' outcomes. The reported arm-level standard errors are 0.013 for the active treatment arms and 0.014 for placebo. The exact number contributing to each analysis is presented with the arm results, but the registry's analysis-population definition also requires specified FEV1 measurements and study medication exposure.

What does a confidence interval communicate?

General: A confidence interval gives a range of values compatible with the data and the method used, reflecting statistical uncertainty in an estimate. It is not a range containing a fixed proportion of individual patient outcomes, nor does it account for every possible source of bias or uncertainty. For a mean difference, an interval that excludes zero is consistent with a nonzero difference under the stated analysis assumptions.

The reported sponsor analyses give 95% confidence intervals for least-squares mean differences. The simple re-calculations also give intervals, constructed from the posted summary statistics. Because the re-calculations use an approximate pooled standard deviation and do not reproduce the sponsor's model, their intervals should be distinguished from the sponsor's model-based intervals.

How are the recalculations different?

General: A simple unadjusted comparison can be reconstructed from arm-level summary estimates and their standard errors. Such a calculation does not adjust for covariates or other model terms unless those are explicitly incorporated. In this analysis, the recalculated standard deviation is approximate, as indicated in the reported comparison details. The comparisons are against placebo and use the posted arm means; they are not the sponsor's mixed-model contrasts.

The recalculated primary comparisons have unadjusted p-values of <0.001. A p-value is a measure of how inconsistent the observed data are with a specified null hypothesis, under the statistical model and assumptions. It is not the probability that the null hypothesis is true, a measure of clinical importance, or a correction for the number of comparisons. The sponsor-reported p-values for its two combination-versus-aclidinium primary contrasts are < 0.001.

Why do the comparisons differ?

The sponsor's reported primary contrasts compare each fixed-dose combination with aclidinium monotherapy, using mixed models and least-squares mean differences. The recalculations compare each arm with placebo using simple summary-statistic methods. Differences between the estimates and intervals are therefore expected: the contrasts, and the statistical methods, are not the same. The registry record does not supply enough model detail to reproduce the sponsor's analysis. Because the discrepancy flag is false, no conflict is identified in the record; the sponsor's own analysis nevertheless takes precedence over a simple re-calculation when describing the sponsor's model-based result.

General: Randomization supports comparison of assigned groups by reducing systematic differences at the start, on average, but it does not remove uncertainty or automatically address missing outcomes, adherence, or all sources of bias. The record identifies a randomized parallel-group design and quadruple masking. It does not report details of the randomization sequence, concealment, or the specific masking procedures, so those features cannot be assessed from this record alone.

The record's named primary analysis population includes randomized patients who took at least one dose and had baseline and at least one post-baseline FEV1 assessment. The primary analysis is thus defined by those conditions. How observations from participants lacking later measurements were handled, whether imputation was used, and whether sensitivity analyses were performed are not reported in the registry record.

11. Confidence Intervals and Precision

The precision of an estimate is reflected partly in the width of its confidence interval: narrower intervals indicate less statistical uncertainty under the analysis method, while wider intervals indicate more. For the recalculated primary comparisons with placebo, the 95% intervals are 0.247 to 0.321 liters for aclidinium/formoterol 400/12 μg, 0.226 to 0.300 liters for 400/6 μg, 0.139 to 0.213 liters for aclidinium, and 0.165 to 0.239 liters for formoterol. These are unadjusted intervals calculated from posted summary statistics, using an approximate pooled standard deviation.

The sponsor's model-based primary intervals are for different contrasts: aclidinium/formoterol 400/12 μg versus aclidinium has a reported 95% interval of 0.073 to 0.144 liters, and 400/6 μg versus aclidinium has a reported 95% interval of 0.052 to 0.123 liters. Their interpretation should remain tied to those comparator groups and to the mixed-model analysis. They should not be read as intervals for combination-versus-placebo differences.

All listed intervals for these comparisons exclude zero, but this does not show whether the estimated differences are large enough to be clinically meaningful. The registry record does not report a threshold for clinical importance. Confidence intervals also do not address all possible limitations, such as uncertainty from missing data, analysis choices, or multiple testing. The full protocol and statistical analysis details needed to evaluate those issues are not reported in the registry record.

The recalculated intervals are not intended to reproduce the sponsor's model-based precision. The sponsor's reported analysis takes precedence for its stated comparisons; the recalculation is useful as a transparent, unadjusted view based on the posted arm summaries.

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 estimates are illustrations based on the observed effect, not the trial's original design calculation. For these continuous outcomes, the figures are participants per arm, not total event counts. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column indicates the estimated participants per arm under those assumptions for an analysis to have an 80% chance of detecting the selected effect if that effect were the true one. The 90% power column gives the analogous planning target for 90% power. These are design-planning probabilities under an assumed effect and model; they are not probabilities that the trial result is true, and they do not describe the trial's achieved power.

Rows for 100% of the observed effect use the observed estimate as the target effect. Rows for 75% and 50% use progressively smaller target effects. Smaller effects are harder to distinguish from random variation, so the planning estimates require more participants per arm. Estimates can vary substantially depending on which endpoint and comparison is used, because their observed effects and variability differ. These figures are not the observed trial sample sizes and are not evidence that the original design used these assumptions. This is not observed power.

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 = 0.284; pooled standard deviation σ = 0.246.
2. n = 2 × (1.96 + 0.842)² × 0.246² / 0.284² = 11.8, rounded up to 12 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 <- 0.284                      # observed difference in means
sigma <- 0.246415538207069                     # 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(1437397)
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 = 12 (80% power), 16 (90% power)
 75% of observed effect: n per arm = 22 (80% power), 29 (90% power)
 50% of observed effect: n per arm = 48 (80% power), 64 (90% power)
power.t.test: 12.9 
Simulated power at n = 12 per arm: 0.771 (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. Analyses Reported by the Sponsor

The registry reports mixed-model analyses for two primary comparisons: aclidinium/formoterol 400/12 μg versus aclidinium and aclidinium/formoterol 400/6 μg versus aclidinium. The reported least-squares mean differences are 0.108 and 0.087 liters, respectively, with 95% confidence intervals of 0.073 to 0.144 and 0.052 to 0.123. Both reported p-values are < 0.001.

The unadjusted recalculations instead compare each active arm with placebo. They use arm-level summary means and standard errors to estimate mean differences, confidence intervals, and p-values, with an approximate pooled standard deviation. Consequently, these results are not an independent reproduction of the sponsor's contrasts: the comparator groups differ, and the sponsor's reported method is a mixed model.

The discrepancy flag is false. Even so, the sponsor's own analysis takes precedence for interpretation of its model-based results. The recalculations can be read as supplementary, unadjusted comparisons against placebo, not as a replacement for the sponsor's analysis or as a direct test of the sponsor-reported contrasts. The full model specification is not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary endpoint and lists secondary outcomes, but it does not report a complete statistical analysis plan. In particular, whether the trial used a prespecified hierarchy or other adjustment for multiple comparisons is not reported in the registry record. This matters because the study includes multiple arms, outcomes, and possible contrasts; interpreting each p-value as though it were the only test can overstate the strength of evidence.

The sponsor-reported analyses give p-values for selected contrasts, and the recalculated values are explicitly unadjusted. The record does not state that the reported p-values have been corrected for multiplicity. The secondary results therefore warrant more caution than a single, prespecified primary comparison, and the available results do not establish how the trial's overall error rate was controlled.

The ITT Population for the primary outcome is defined as randomized patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment. The registry does not report how many randomized patients did not meet those criteria, how missing values were handled, or whether sensitivity analyses evaluated alternative assumptions about missing data. These details are not reported in the registry record.

The record reports arm sizes alongside outcome estimates, but those figures do not explain the completeness of measurements at each visit or the handling of withdrawals. A stated analysis population and reported arm summaries do not by themselves establish that missing outcomes had no effect on the estimates. The protocol's original sample-size justification, interim-analysis plan, and full model specification are also not reported in the registry record. Conclusions about those design and analysis features should therefore be limited to the information explicitly recorded.

16. 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: pneumonia (0.9%), atrial fibrillation (0.6%), cerebrovascular accident (0.6%), angina pectoris (0.6%), myocardial infarction (0.6%).

The safety results list participants at risk and the number with serious adverse events and other adverse events by arm. For serious adverse events, the posted figures are 19 of 335 for aclidinium/formoterol 400/12 μg, 18 of 333 for 400/6 μg, 17 of 337 for aclidinium, 15 of 332 for formoterol, and 12 of 332 for placebo. The other-adverse-event figures are 63 of 335, 65 of 333, 57 of 337, 74 of 332, and 58 of 332, respectively. These are counts reported for each arm; they should not be added across arms or interpreted as numbers of unique events.

The registry lists pneumonia at 0.9% among the top serious adverse event terms. Atrial fibrillation, cerebrovascular accident, angina pectoris, myocardial infarction, and transient ischaemic attack are each listed at 0.6%. These terms and percentages describe the posted record and do not establish comparative risk or causality. Death counts are not reported in the registry record. Further detail on event definitions, timing, severity, and statistical comparisons is not reported in the registry record, so the figures alone do not provide a complete safety assessment.

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

The posted primary results show positive mean FEV1 changes in the combination and monotherapy arms, while the placebo arm has a negative mean change. The simple recalculations estimate positive mean differences for each active arm compared with placebo, with unadjusted p-values of <0.001. The sponsor's model-based analyses report positive differences for both fixed-dose combinations compared with aclidinium, with 95% confidence intervals excluding zero and reported p-values of < 0.001.

These are statistical descriptions of selected group-average outcomes at Week 24. They do not show that every participant experienced a change matching the arm mean, and they do not establish the response of an individual patient. Statistical evidence against a zero difference is also distinct from evidence that a difference is clinically important. The registry record does not report a threshold for clinically meaningful change in FEV1, TDI, or SGRQ.

The findings are limited to the population and measurements specified in the record, including the primary ITT Population definition and the one-hour morning post-dose FEV1 assessment. The reported treatment period was 24 weeks; the results do not by themselves establish effects after that period. The record does not provide a complete account of missing-data handling, multiplicity control, or all model details.

These results should not be read as medical advice or as a complete judgment of treatment effects. The available results describe estimated changes, selected comparisons, and their statistical uncertainty. They do not establish effects on outcomes not measured or reported, and they do not settle the balance of benefits and harms for any particular person.

18. Why This Trial Matters Statistically

This trial is statistically informative because it includes combination treatment, each listed monotherapy, and placebo within a randomized parallel-group design. That structure makes the choice of comparator especially important. A combination-versus-placebo difference addresses a different question from a combination-versus-component-medicine difference; treating them as interchangeable would misstate what the comparison estimates.

The record also illustrates why model-based results and simple recalculations should be kept distinct. The sponsor reports mixed-model comparisons against aclidinium, while the recalculations use posted summary statistics to compare arms with placebo. Both may be useful for understanding the data, but they target different contrasts and rely on different methods. The sponsor's analysis takes precedence for its stated model-based comparisons.

Precision and interpretation matter alongside p-values. The results include confidence intervals and arm-level standard errors, allowing uncertainty to be considered rather than relying only on a threshold for statistical significance. Yet an interval that excludes zero does not establish clinical importance, and a collection of secondary tests raises questions about multiplicity when adjustment plans are not reported.

Finally, the registry's definition of the primary analysis population clarifies who contributed to the stated endpoint analysis, while the absence of full missing-data and model details limits independent assessment. Reading those design and reporting features together supports a more measured interpretation than focusing on statistical significance alone.

19. 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 the available record affect interpretation. The primary endpoint is restricted to one-hour morning post-dose FEV1 at Week 24; the registry does not report other primary time points or a threshold for clinical importance. The primary analysis population excludes randomized patients who did not take study medication or did not have the stated FEV1 assessments, but counts of those not included are not reported in the registry record.

The sponsor's reported primary comparisons are between each combination and aclidinium, whereas the simple recalculations compare each arm with placebo. The recalculated standard deviation is approximate and the calculations are unadjusted, so they should not be mistaken for the sponsor's model-based estimates. The complete model specification is not reported in the registry record.

The record does not report the method for handling missing outcome data, sensitivity analyses, multiplicity adjustment, the original sample-size justification, or interim-analysis details. It also does not report the clinical-importance thresholds for the primary or secondary outcomes. Although serious and other adverse-event counts are listed, deaths are not reported in the registry record, and further event-level safety details are not available in the record.

The listed secondary outcomes address dyspnea and respiratory health status, but only those outcomes and selected comparisons are included. The registry results therefore do not provide a comprehensive account of all outcomes that may have been measured. These reporting limitations do not demonstrate that the underlying trial lacked such methods or data; they mean those details are not reported in the registry record.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Efficacy, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide and Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) — NCT01437397.
• Registry record last updated 2017-03-23; status last verified 2017-01.
• Results first posted 2017-03-23.
• 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.

23. Record Summary

NCT01437397 is a completed Phase III randomized, parallel-group, quadruple-masked, placebo-controlled study sponsored by AstraZeneca. It enrolled 1692 patients with moderate to severe, stable COPD and compared two aclidinium/formoterol fixed-dose combinations with aclidinium, formoterol, and placebo. The study record lists a 24-week treatment period, a run-in period, and a two-week follow-up visit; the run-in duration is not reported in the registry record.

The primary endpoint was change from baseline in one-hour morning post-dose FEV1 at Week 24. Sponsor-reported mixed-model analyses compare the combination arms with aclidinium, while recalculated unadjusted comparisons use placebo as the comparator. The record also reports TDI and SGRQ secondary outcomes and arm-level adverse-event counts. Details including multiplicity control, missing-data handling, and the original sample-size justification are not reported in the registry record.