Efficacy and Safety of Four Doses of Glycopyrronium Bromide (NVA237) in Patients With Stable Chronic Obstructive Pulmonary Disease (COPD), in Comparison to an Active Comparator Tiotropium: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Four Doses of Glycopyrronium Bromide (NVA237) in Patients With Stable Chronic Obstructive Pulmonary Disease (COPD), in Comparison to an Active Comparator Tiotropium (NCT00501852), a randomized phase 2 study. The primary outcome is Trough Forced Expiratory Volume in 1 Second (FEV1) Following 7 Days of Treatment.

2. Clinical Question

3. Trial Design

This was a randomized, phase 2, multi-center, multiple-dose crossover study in people with stable COPD. The registry lists enrollment of 83 participants and describes an incomplete-block design with four treatment periods. Participants were randomized to one of 30 treatment sequences. The NVA237 doses and placebo were given through a single-dose dry-powder inhaler for seven days per treatment period. Tiotropium 18 µg once daily was delivered by Handihaler and was open-label.

A seven-day washout period separated each sequence, according to the arm descriptions. In a crossover study, a participant may receive more than one treatment over separate periods. This structure can allow comparisons within participants, but it also means that period, sequence, and possible carryover effects can matter to the analysis. How those design features were handled statistically is not reported in the registry record.

The study record lists quadruple masking overall, while specifically identifying tiotropium as open-label. Those details describe different aspects of the study and should be read together rather than interpreted as evidence that every treatment was masked in the same way. The record does not report how masking was implemented for each role.

The study status is completed. Its primary completion is listed as 2007-12, and its start is listed as 2007-07. The primary outcome was trough FEV1 on Day 7 in the modified intent-to-treat population. Participants in that population were analyzed according to the treatment they received. The record does not report the number randomized to each sequence or an account of participants who did not contribute to each treatment-period estimate.

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: Modified Intent-to-Treat (mITT) population. The modified intent-to-treat (mITT) population included all randomized patients who received at least one dose of study drug. Patients were analyzed according to the treatment they received.

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 Trough Forced Expiratory Volume in 1 Second (FEV1) Following 7 Days of Treatment, measured over Day 7.

The primary endpoint was trough forced expiratory volume in one second (FEV1), measured in liters after seven days of treatment. FEV1 measures the amount of air that can be forcibly exhaled from the lungs during the first second of a forced exhalation. It is obtained using spirometry. The registry defines the trough value as the mean of two measurements taken 23h 15min and 23h 45min after dosing.

A trough measurement is intended to represent lung function near the end of the dosing interval, rather than a measurement taken soon after a dose. That makes it relevant to a study assessing daily treatment across a dosing period. This is a general explanation of the endpoint concept, not a claim about the clinical importance of any particular difference observed in this trial.

The registry reports least-squares mean FEV1 values at Day 7, with standard errors for the treatment groups. It also gives estimated mean differences and confidence intervals for comparisons with placebo. The name “least-squares mean” indicates a model-based mean, but the model specification and its handling of the crossover design are not reported in the registry record. FEV1 is a continuous measure, so the posted values describe average measurements rather than counts of participants with or without an event.

7. Results Posted in the Registry

• NVA237 12.5 ug: mean 1.32 versus 1.24 on control; difference 0.07 (95% CI 0.03 to 0.12), standardized effect d = 0.68; z-test p = <0.001.
• NVA237 25 ug: mean 1.33 versus 1.24 on control; difference 0.09 (95% CI 0.05 to 0.13), standardized effect d = 0.83; z-test p = <0.001.
• NVA237 50 ug: mean 1.37 versus 1.24 on control; difference 0.13 (95% CI 0.09 to 0.17), standardized effect d = 1.21; z-test p = <0.001.
• NVA237 100 ug: mean 1.39 versus 1.24 on control; difference 0.14 (95% CI 0.10 to 0.18), standardized effect d = 1.31; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a least-squares mean describe?

A least-squares mean is a model-based estimate of an average. It is often used when an analysis adjusts for design features or other variables, so it need not equal a simple arithmetic average of the observed values. The registry names the primary results as least-squares means and reports standard errors, but it does not report the model terms, adjustment variables, or estimation method. The values can be described as posted model-based means; the exact adjustments cannot be inferred from the label alone.

What is a mean difference?

A mean difference expresses the contrast between two group means in the outcome’s units. Here, the posted comparison estimates are in liters and use placebo as the reference for each listed dose and for tiotropium. A positive contrast means the estimated FEV1 value for the named treatment is above the placebo estimate in that posted comparison. The recalculated contrasts are simple unadjusted re-calculations from summary statistics. They are not a substitute for a reported model that accounts for the crossover structure.

How should the crossover structure affect interpretation?

In a parallel-group design, participants generally remain in one assigned group. In a crossover design, participants can receive different treatments in different periods. General statistical reasoning: measurements from the same participant are often correlated, so analyses may need to account for that dependence rather than treat every treatment-period observation as independent. Sequence and period can also be relevant, and carryover is a concern if a prior treatment affects a later period. The registry describes four periods, 30 sequences, and a seven-day washout, but it does not report the primary model or how it handled those considerations.

The term incomplete block means that the design does not require every participant to receive every treatment in the full set. The registry’s four-period description alongside the treatment options is consistent with an incomplete-block crossover, but the precise allocation of treatments to each sequence is not reported in the registry record. Consequently, the group-specific counts should not be read as independent parallel-arm sample sizes.

What do standard errors tell the reader?

A standard error describes the estimated sampling uncertainty of an estimate under the model or calculation used. Smaller standard errors indicate more precise estimates under that analysis, while larger ones indicate greater sampling uncertainty. The registry reports standard errors for the least-squares means: 0.015 for NVA237 12.5 µg, 0.015 for NVA237 25 µg, 0.015 for NVA237 50 µg, 0.015 for NVA237 100 µg, 0.016 for placebo, and 0.015 for tiotropium. The record does not identify the exact model-based method used to obtain them.

A confidence interval gives a range of values compatible with the observed data under the assumptions of the calculation. It conveys uncertainty about an estimated contrast, not the range of individual participants’ responses. The placebo-comparison intervals are all entirely above zero. This is consistent with the posted unadjusted p-values of <0.001, but the registry does not report a multiplicity-adjusted inference. Because the comparisons are recalculated from summary statistics, their intervals should not be assumed to reproduce a trial-specific crossover model.

Why does over-dispersion matter?

General explanation: over-dispersion occurs when observed variation is greater than a statistical model expects. If it is ignored, standard errors can be too small and confidence intervals too narrow, making results appear more precise than they are. The registry record does not report an over-dispersion assessment, and the posted continuous endpoint is not accompanied by details that permit one to evaluate this issue. Over-dispersion is not asserted to have occurred in this trial.

What is not specified about the analysis?

The registry identifies the endpoint, the population, the treatment summaries, and the posted comparisons. It does not report the planned statistical analysis, the primary model, a test of dose response, assumptions about missing outcome measurements, imputation procedures, or a multiplicity procedure. The number of posted analyses is recorded as zero, despite the presence of outcome summaries and comparison values; the registry does not explain that recording. It also does not report an original sample-size justification or planned power. The uncertainty about these elements limits independent evaluation of whether the posted statistical calculations match the original trial analysis.

10. Confidence Intervals and Precision

The confidence intervals describe uncertainty around the posted mean differences from placebo. For NVA237 12.5 µg, the estimate is 0.074 L and the interval is 0.032 to 0.116. For NVA237 25 µg, the estimate is 0.09 L and the interval is 0.047 to 0.133. For NVA237 50 µg, the estimate is 0.131 L and the interval is 0.089 to 0.173. For NVA237 100 µg, the estimate is 0.142 L and the interval is 0.100 to 0.184. For tiotropium, the estimate is 0.127 L and the interval is 0.085 to 0.169.

All of these intervals lie above zero, which indicates that the posted estimates are positive relative to placebo across the intervals’ ranges. Their width conveys the precision of each estimated contrast: a narrower interval means less sampling uncertainty under the assumptions used to calculate it. The intervals do not show the distribution of individual FEV1 values, and they do not guarantee that the true contrast lies within the interval.

These intervals accompany recalculated, unadjusted comparisons based on posted summary statistics. They may not reflect the analysis that would result from a model incorporating within-participant correlation and other crossover features. The registry record does not report a confidence interval for a direct NVA237-versus-tiotropium contrast, nor does it report a procedure for adjusting uncertainty across the multiple placebo comparisons. The precision of the posted estimates should therefore be understood in the context of those limitations, not as a complete account of uncertainty under the original trial analysis.

11. 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 figures are illustrations based on the observed effect, not the trial’s original design calculation. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Each planning scenario asks how many participants per arm would be needed to detect a stated fraction of the observed effect. The listed scenarios use 100%, 75%, and 50% of the observed effect.

The 80% power column describes the planning sample size at which the assumed analysis would have an 80% chance of detecting the specified effect under the planning assumptions, if that effect and those assumptions were correct. The 90% power column makes the same kind of calculation for a 90% chance. These are planning probabilities, not guarantees for a future study. The calculations are two-arm illustrations and do not reproduce the incomplete-block crossover structure described for this trial.

For example, the NVA237 50 µg comparison uses 11 participants per arm for 80% power and 15 participants per arm for 90% power when planning for 100% of the observed effect. For 75% of the observed effect, the corresponding figures are 20 and 26; for 50% of the observed effect, they are 44 and 58. Other comparisons have their own planning values because the observed effects differ.

Smaller effects require more participants to detect under the same planning assumptions. The figures are not observed power: they do not measure the probability that this completed trial detected its effects. The original sample-size assumptions and justification are not reported in the registry record.

12. 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 = 0.074; pooled standard deviation σ = 0.108.
2. n = 2 × (1.96 + 0.842)² × 0.108² / 0.074² = 33.6, rounded up to 34 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 <- 0.0739999999999998                      # observed difference in means
sigma <- 0.108321653367345                     # 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(501852)
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 = 34 (80% power), 46 (90% power)
 75% of observed effect: n per arm = 60 (80% power), 81 (90% power)
 50% of observed effect: n per arm = 135 (80% power), 181 (90% power)
power.t.test: 34.6 
Simulated power at n = 34 per arm: 0.792 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple treatment comparisons with placebo: four NVA237 doses and tiotropium. Each posted unadjusted p-value is <0.001, but the registry record does not report a method for adjusting inference across those comparisons. When several hypotheses are tested, the chance of at least one false-positive result can increase; multiplicity procedures are used to address that general issue. This is a general statistical explanation, not evidence that a particular procedure was or was not used in the original analysis.

The record does not report the primary statistical analysis plan, the model specification, any hierarchy or ordering of hypotheses, or whether a dose-response test was planned. Nor does it report interim analyses or stopping rules. Such details should not be inferred from the posted p-values or endpoint values. The registry records zero analyses, but gives outcome estimates and contrasts; it does not explain this apparent difference in reporting.

The primary population is defined as randomized participants who received at least one dose, analyzed according to treatment received. The registry does not report how missing Day 7 measurements were handled, whether any imputation was used, the number excluded from each treatment-period analysis, or how participants with incomplete treatment sequences contributed to the endpoint estimates.

Because the design is a crossover, an analysis may need to account for repeated measurements within participants, treatment sequence, and period. The registry does not report whether these features were included in the primary model, or whether carryover was assessed. It also does not describe the calculation of the least-squares means beyond naming the summary type. These omissions prevent reconstruction of the trial’s intended analysis and make the unadjusted recalculated contrasts unsuitable as a replacement for a fully specified crossover analysis.

14. 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: gastric cancer (1.9%).

The safety counts are organized by treatment, with the number at risk and the number affected reported for serious and other adverse events. The serious adverse event counts were 0 among 55 participants for NVA237 12.5 µg, 0 among 51 for NVA237 25 µg, 1 among 53 for NVA237 50 µg, 0 among 54 for NVA237 100 µg, 0 among 55 for placebo, and 0 among 54 for tiotropium. The registry lists gastric cancer at 1.9% among the top serious-event terms.

These are descriptive counts within a short, seven-day treatment-period study. The treatment-specific numbers at risk are not the total trial enrollment and should not be added to infer the number of unique participants, because the design was crossover. The registry does not report deaths for these groups; death counts are therefore not reported in the registry record. The counts alone do not establish comparative safety, particularly without event timing, exposure-adjusted analyses, or fuller information on how events were attributed across crossover periods.

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

The registry results describe Day 7 trough FEV1 estimates for four NVA237 doses, placebo, and tiotropium in the modified intent-to-treat population. The posted treatment means range from 1.243 L for placebo to 1.385 L for NVA237 100 µg. The recalculated placebo contrasts are positive for all four NVA237 doses, with confidence intervals entirely above zero and unadjusted p-values of <0.001. The tiotropium comparison with placebo is also positive in the posted results.

Those results do not by themselves establish a treatment recommendation or determine the clinical importance of the differences. The registry record does not give a threshold for a clinically meaningful FEV1 difference, and it does not report longer-term outcomes. The study assessed a short treatment duration and a lung-function endpoint; it does not, in the posted material, quantify effects on symptoms, exacerbations, quality of life, or other clinical outcomes.

The findings also do not establish a direct difference between NVA237 and tiotropium. The listed contrasts use placebo as the comparator, and no direct NVA237-versus-tiotropium estimate is reported. Nor can the observed ordering of NVA237 means be treated as a formally demonstrated dose-response relationship without details of a planned and performed dose-response analysis.

Finally, the comparisons are simple unadjusted recalculations from posted summary statistics. The original crossover model, missing-data handling, and multiplicity procedure are not reported in the registry record. These features matter when interpreting uncertainty and statistical evidence. The posted numbers therefore support a description of the recorded estimates, but not a full reconstruction of the trial’s analysis or broader conclusions about outcomes beyond those measured.

16. Why This Trial Matters Statistically

This trial illustrates how a crossover design can make a dose-ranging study efficient in concept: participants may contribute observations under more than one treatment, rather than belonging to only one treatment group. That feature can be useful when within-participant comparisons are relevant, but it also makes the analysis dependent on how repeated measurements, treatment periods, sequences, and possible carryover are handled. The registry identifies the crossover structure but does not report the details of the model used for the primary endpoint.

The study also shows why statistical summaries need to be interpreted with their comparator and endpoint in view. The registry gives least-squares mean FEV1 values and placebo contrasts for four NVA237 doses, as well as a placebo contrast for tiotropium. Those estimates address the specified Day 7 lung-function outcome; they do not themselves answer whether the treatments differ directly from each other or whether a particular difference is clinically important.

From a reporting perspective, the endpoint means and uncertainty estimates are useful, but the record leaves important analytic details unspecified. The lack of a reported multiplicity procedure, crossover-model specification, missing-data approach, and original sample-size rationale limits independent assessment of the inferential framework. The planning illustrations can help readers understand how assumed effect size and power relate to participant counts, but they are not a substitute for the study’s original design justification.

For biostatisticians and clinical researchers, the central lesson is to distinguish observed summaries, recalculated comparisons, and the original prespecified analysis. Each can answer a different question, and only the first two are available in sufficient detail in the registry record.

17. 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 reports a completed phase 2 crossover study, but the primary analysis model and its treatment of the crossover design are not described. This is important because measurements across treatment periods from the same participant may be related. The handling of period and sequence effects, carryover, and within-participant correlation is not reported.

The primary outcome is trough FEV1 after seven days, and the record gives group-specific least-squares means and standard errors. It does not report the model terms used to obtain the least-squares means or a complete analysis plan. The posted comparisons are recalculated, unadjusted contrasts from summary statistics; they should not be taken as a reconstruction of a trial-specific model.

The registry does not report how missing outcome measurements were handled, why the treatment-specific analysis counts vary, or the number of participants contributing complete crossover data. The modified intent-to-treat population includes randomized participants who received at least one dose and analyzes them according to treatment received, but further detail about period-level inclusion is not reported.

The record includes multiple placebo comparisons without a stated multiplicity procedure. It does not report the original sample-size justification, planned interim analyses, or dose-response testing. Finally, the study’s primary measurement followed seven days of treatment; longer-term outcomes are not described in the posted primary result. These limitations constrain interpretation of precision, direct treatment comparisons, and outcomes beyond Day 7 FEV1.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Efficacy and Safety of Four Doses of Glycopyrronium Bromide (NVA237) in Patients With Stable Chronic Obstructive Pulmonary Disease (COPD), in Comparison to an Active Comparator Tiotropium — NCT00501852.
• Registry record last updated 2012-05-08; status last verified 2010-12.
• Results first posted 2011-01-21.
• 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.

21. Record Summary

NCT00501852 is a completed phase 2 randomized, multi-center crossover study in people with stable COPD. Enrollment was 83. The study compared four daily doses of NVA237 with placebo and included open-label tiotropium 18 µg once daily as an active comparator. Treatment periods lasted seven days, and the arm descriptions specify a seven-day washout between sequences.

The primary endpoint was trough FEV1 in liters at Day 7, defined as the mean of two measurements taken 23h 15min and 23h 45min after dosing. The registry reports least-squares means in the modified intent-to-treat population and comparisons with placebo. The posted comparisons are unadjusted recalculations, and the primary statistical model, multiplicity approach, and missing-data handling are not reported in the registry record.

Serious adverse event counts are reported by treatment, with one affected participant recorded for NVA237 50 µg and zero for the other listed groups. Death counts are not reported in the registry record.