Study to Compare the Efficacy and Safety of QVM149 With QMF149 in Patients With Asthma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Compare the Efficacy and Safety of QVM149 With QMF149 in Patients With Asthma (NCT02571777), a randomized phase 3 study. The primary outcome is Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 Versus QMF149 at Week 26.

2. Clinical Question

This was a Phase 3 trial with 3092 participants enrolled. The registry record describes a randomized, parallel-group study lasting 52 weeks. Its central efficacy question concerns a lung-function measure rather than a direct measure of symptoms or daily functioning. The registry record also lists asthma-control and other respiratory-function outcomes as secondary measures, but those outcomes address related, distinct questions.

3. Trial Design

The registry record identifies NCT02571777 as a Phase 3, randomized, parallel-group study sponsored by Novartis Pharmaceuticals. It lists 3092 participants as enrolled. The recorded start date is 2015-12-08, the primary completion date is 2019-06-14, and the overall status is completed. The official title describes a multicenter, 52-week, double-blind, active-controlled study; the registry masking field specifies quadruple masking. Both descriptions indicate masking, but the record does not explain the relationship between the title wording and the masking field.

Five treatment groups are listed: QVM149 150/50/160 μg once daily, QVM149 150/50/80 μg once daily, QMF149 150/320 μg once daily, QMF149 150/160 μg once daily, and salmeterol/fluticasone 50/500 μg twice daily. The QVM149 and QMF149 regimens were delivered using Concept1; salmeterol/fluticasone was delivered using Accuhaler. The primary endpoint description identifies two planned dose-pair questions: QVM149 150/50/80 μg versus QMF149 150/160 μg, and QVM149 150/50/160 μg versus QMF149 150/320 μg.

The primary measure was trough FEV1 at Week 26, analyzed in the full analysis set among participants with a valid outcome measurement. The registry record also includes other lung-function and asthma-control measures, including outcomes assessed at Week 52. The posted primary outcome arm counts range from 602 to 614, while safety counts at risk range from 608 to 618. These are outcome-specific or safety-analysis counts, not a replacement for the overall enrollment figure. More detailed information on allocation procedures, stratification, eligibility criteria, treatment adherence, and the original sample-size justification is 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: 4851 participants were screened of which 3092 participants were randomized to 1 of the 5 treatment groups with a randomization ratio of 1:1:1:1:1.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS including patients with a valid measurement for the outcome measure.

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: Randomized Set (RAN) consisted of all participants who were assigned a randomization number, regardless of whether or not they actually received study medication.

6. Primary Endpoint

The registry lists the primary outcome as Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 Versus QMF149 at Week 26, measured over 26 weeks.

The primary endpoint was trough forced expiratory volume in one second (FEV1) at Week 26, measured in litres. FEV1 is the amount of air forcibly exhaled from the lungs during the first second of a forced exhalation. For this trial, trough FEV1 was defined as the average of two spirometry measurements taken 23 hr 15 min and 23 hr 45 min after the evening dose. The timing makes the measure a standardized assessment late in the dosing interval.

FEV1 is used as an objective measure of lung function. Comparing group averages can describe how the treatments differed on this particular spirometric outcome at the specified time. It does not, by itself, capture every dimension of asthma control, symptoms, daily activity, or safety. The registry record lists separate secondary outcomes for asthma-control questionnaire scores, peak flow, forced vital capacity, other lung-function measures, and symptom-free or symptom-free-day percentages.

The primary endpoint was summarized as a least-squares mean with a standard error. The sponsor’s posted analyses use a mixed model for repeated measures and report treatment contrasts with 95% confidence intervals. The analysis population is described as the full analysis set with a valid measurement for the outcome. The registry record does not report the full endpoint analysis specification, including all model covariates, handling of intercurrent events, or the missing-data assumptions used in the sponsor analysis.

7. Results Posted in the Registry

• QVM149 150/50/80 µg o.d.: mean 2.03 versus 2.05 on control; difference -0.02 (95% CI -0.06 to 0.01), standardized effect d = -0.07; z-test p = 0.248.
• QMF149 150/320 µg o.d.: mean 1.98 versus 2.05 on control; difference -0.07 (95% CI -0.10 to -0.03), standardized effect d = -0.21; z-test p = <0.001.
• QMF149 150/160 µg o.d.: mean 1.95 versus 2.05 on control; difference -0.10 (95% CI -0.13 to -0.06), standardized effect d = -0.30; z-test p = <0.001.
• Salmeterol/Fluticasone 50/500 μg b.i.d.: mean 1.93 versus 2.05 on control; difference -0.12 (95% CI -0.16 to -0.08), standardized effect d = -0.38; 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.

Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 Versus Salmeterol/Fluticasone at Week 26

• 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:
  • QVM149 150/50/80 µg o.d.: mean 2.03 versus 2.05 on control; difference -0.02 (95% CI -0.06 to 0.01), standardized effect d = -0.07; z-test p = 0.248.
  • QMF149 150/320 µg o.d.: mean 1.98 versus 2.05 on control; difference -0.07 (95% CI -0.10 to -0.03), standardized effect d = -0.21; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between QVM149 150/50/80 µg o.d. and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for QMF149 150/320 µg o.d. than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Trough FEV1 at Week 52

• 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:
  • QVM149 150/50/80 µg o.d.: mean 1.99 versus 2.05 on control; difference -0.06 (95% CI -0.09 to -0.02), standardized effect d = -0.18; z-test p = 0.002.
  • QMF149 150/320 µg o.d.: mean 1.97 versus 2.05 on control; difference -0.08 (95% CI -0.12 to -0.05), 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 QVM149 150/50/80 µg o.d. 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 QMF149 150/320 µg o.d. than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Trough Forced Expiratory Flow (FEF) Between 25% and 75% of FVC (FEF25-75) at 52 Weeks

• 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:
  • QVM149 150/50/80 µg o.d.: mean 1.26 versus 1.35 on control; difference -0.09 (95% CI -0.14 to -0.04), standardized effect d = -0.19; z-test p = <0.001.
  • QMF149 150/320 µg o.d.: mean 1.26 versus 1.35 on control; difference -0.09 (95% CI -0.15 to -0.04), standardized effect d = -0.20; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for QVM149 150/50/80 µg o.d. 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 QMF149 150/320 µg o.d. than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry record lists 23 posted secondary outcomes, spanning asthma control, spirometry, peak expiratory flow, and symptom-related measures. The displayed secondary results include Week 26 FEV1 comparisons with salmeterol/fluticasone, Week 52 FEV1, and a measure of forced expiratory flow. The sponsor-reported analyses for several of these outcomes show positive model-based contrasts for selected QVM149 comparisons, with reported confidence intervals and p-values. The broader collection of outcomes therefore addresses whether patterns in lung function and asthma control are consistent with the primary endpoint, while also examining distinct aspects of respiratory status.

Secondary outcomes are not interchangeable with the primary endpoint. They can add context, but a result on one measure does not prove the same effect on another. Nor do related lung-function measures independently establish changes in symptoms or daily life. The registry record includes outcome names and selected results, but a full account of the prespecified hierarchy and all analysis decisions is not reported in the registry record.

Unadjusted secondary results carry less weight when many outcomes, visits, or treatment contrasts are considered. General statistical explanation: testing many hypotheses increases the chance that at least one result appears statistically significant by chance, unless the analysis plan controls that risk. The record does not report whether multiplicity adjustments were applied across secondary outcomes. Consequently, secondary p-values should be read as individual reported tests rather than definitive evidence across the entire outcome set. Their main contribution is contextual and hypothesis-generating unless the complete prespecified testing strategy supports stronger claims.

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

• Asthma Control Questionnaire (ACQ-7) at Week 26 and Week 52
• Trough Forced Expiratory Volume in 1 Second (Trough FEV1) of QVM149 Versus Salmeterol/Fluticasone at Week 26
• Trough FEV1 at Week 52
• Pre-dose Forced Vital Capacity (FVC) at Week 4 and Week 12
• Trough Forced Expiratory Flow (FEF) Between 25% and 75% of FVC (FEF25-75) at 52 Weeks
• Change From Baseline in Morning and Evening Peak Expiratory Flow Rate (PEF) Over 26 and 52 Weeks of Treatment
• Change From Baseline in Percentage of Asthma Symptom-free Days Over 52 Weeks
• Change From Baseline in Percentage of Days With no Daytime Symptoms Over 52 Weeks

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: each valid measurement is a quantity in litres, and the reported arm summaries are least-squares means. A mean describes the central level of a continuous measurement in a group. A least-squares mean is a model-based group estimate; it may account for features of the statistical model and therefore need not be identical to a simple arithmetic average. The registry record identifies the sponsor’s reported parameter as an LS Mean and names mixed model for repeated measures (MMRM) as the analysis method.

What does a repeated-measures model do?

General statistical explanation: repeated-measures models are designed for outcomes measured on participants at more than one time point. Measurements from the same person can be correlated, so treating every measurement as independent may misrepresent the uncertainty. An MMRM models the pattern of repeated observations and can estimate treatment contrasts at a particular visit while using information across visits. The exact model structure, covariance specification, covariates, and missing-data assumptions used for this trial are not reported in the registry record. The method name alone does not reveal those details.

The sponsor’s primary contrasts compare the QVM149 dose groups with their corresponding QMF149 dose groups. The reported Week 26 estimates are 0.065 L and 0.076 L, each with a 95% confidence interval and p-value. The values are model-based contrasts, not merely differences between the displayed arm means. The registry record’s sponsor analyses should therefore be distinguished from the unadjusted recalculations, which use posted summary statistics and a different reference-arm comparison structure.

Why are the recalculations different?

The recalculated comparisons use QVM149 150/50/160 μg as a common reference for the other arms. The primary protocol question, as described in the registry record, instead pairs QVM149 150/50/160 μg with QMF149 150/320 μg, and QVM149 150/50/80 μg with QMF149 150/160 μg. A reference-arm comparison can be useful as a simple reading of the arm summaries, but it is not interchangeable with the sponsor’s two dose-matched contrasts. The recalculations are also unadjusted and use an approximate pooled standard deviation derived from the reported standard errors. Because the discrepancy flag is true, the sponsor’s own analysis takes precedence for interpretation of the trial’s primary comparisons.

General statistical explanation: a standard error describes the estimated sampling variability of an estimate, whereas a standard deviation describes the spread of individual observations. A confidence interval combines an estimate and its uncertainty to give a range of values compatible with the analysis and its assumptions. A p-value measures how unusual data at least as incompatible with a null hypothesis would be under that hypothesis and the specified model. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect.

How should the p-values be read?

The sponsor reports p < 0.001 for each primary dose-pair comparison. This indicates that the model-based results are statistically inconsistent with a zero contrast under the tested analysis, at the precision reported. The registry record does not state whether or how the primary comparisons were adjusted for multiplicity. Without that information, the p-values should be read as the reported results for each contrast, not as a complete account of family-wise error control across all planned tests.

The recalculated p-values are explicitly unadjusted. An unadjusted test does not account for the number of comparisons being considered. The recalculated comparison of the lower QVM149 dose against the reference has p = 0.248 and a confidence interval that includes zero. That result concerns a different contrast from the sponsor’s primary comparison of the lower QVM149 dose with QMF149 150/160 μg. The calculations should not be used to replace or relabel the sponsor’s stated primary analyses.

What do the planning illustrations represent?

The sample-size figures are planning illustrations based on stated fractions of the observed effect, not the trial’s original design calculations. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustration asks how many participants per arm would be needed to detect the stated fraction of the observed effect at 80% or 90% power. The trial’s own design assumptions and sample-size justification are not reported in the registry record. These planning figures are separate from the observed enrollment and do not establish whether the study was adequately designed for every outcome or contrast.

11. Confidence Intervals and Precision

The sponsor’s 95% confidence interval for the QVM149 150/50/160 μg versus QMF149 150/320 μg primary contrast runs from 0.031 to 0.099 L around the reported estimate of 0.065 L. For QVM149 150/50/80 μg versus QMF149 150/160 μg, the interval runs from 0.041 to 0.111 L around the estimate of 0.076 L. Both intervals are entirely above zero, matching the reported p-values of < 0.001.

General statistical explanation: a confidence interval expresses uncertainty around an estimate under the analysis model. A narrower interval indicates greater precision for that estimated contrast than a wider interval would, while the interval’s location indicates which values remain compatible with the data and model. A 95% confidence interval is not a guarantee that the true effect lies in that specific interval, nor does it describe the range of individual participant outcomes.

The arm-level standard errors for Week 26 range from 0.013 to 0.013 L. These quantify uncertainty in the estimated arm means, not variation among individual participants. The sponsor’s confidence intervals pertain to modeled between-group contrasts and are the more direct precision summaries for the primary questions. The recalculated intervals are based on simple unadjusted comparisons and are not substitutes for the sponsor’s intervals.

Precision is not the same as clinical importance. The registry record does not report a threshold defining a clinically important FEV1 difference, so the intervals cannot be classified against such a threshold from the record alone. Precision also does not address possible bias from missing data, model choices, or multiplicity. The full statistical analysis plan and details needed to assess those issues are not reported in the registry record.

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 sample-size figures are planning illustrations for two-arm comparisons. The values are participants per arm, not total participants, for the continuous outcomes in this analysis. The stated calculation assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. Time-to-event displays, if present, use total event counts, but those are not the basis for the continuous FEV1 comparisons.

The 80% power column represents the number of participants per arm associated with an 80% chance of detecting the specified effect under the planning assumptions, if that effect and the assumptions hold. The 90% power column represents the corresponding planning count for a 90% chance. These are design concepts, not probabilities that the observed finding is correct. The trial’s original sample-size assumptions and justification are not reported in the registry record.

Rows that plan for a smaller fraction of the observed effect generally require more participants per arm than rows using the full observed effect. This occurs because smaller differences are harder to distinguish from sampling variability. The illustrations vary by comparison because the observed effects used as their starting points differ. The figures are not observed power: observed power is not an appropriate way to interpret a result after the data have been collected, and these calculations are prospective planning illustrations rather than a summary of the trial’s achieved performance.

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 = -0.021; pooled standard deviation σ = 0.318.
2. n = 2 × (1.96 + 0.842)² × 0.318² / -0.021² = 3,608.9, rounded up to 3,609 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 <- -0.0209999999999999                      # observed difference in means
sigma <- 0.318412860921163                     # 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(2571777)
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 = 3,609 (80% power), 4,832 (90% power)
 75% of observed effect: n per arm = 6,416 (80% power), 8,590 (90% power)
 50% of observed effect: n per arm = 14,436 (80% power), 19,326 (90% power)
power.t.test: 3609.9 
Simulated power at n = 3,609 per arm: 0.798 (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 sponsor’s reported primary results come from mixed models for repeated measures and address the two intended dose-pair comparisons. The reported contrasts are 0.065 L for QVM149 150/50/160 μg versus QMF149 150/320 μg and 0.076 L for QVM149 150/50/80 μg versus QMF149 150/160 μg. Each has a reported 95% confidence interval entirely above zero and p < 0.001.

The simple recalculations are unadjusted comparisons based on the posted arm summary statistics. They use QVM149 150/50/160 μg as the reference arm, so they do not match the sponsor’s planned pairing for the lower-dose QVM149 comparison. They also do not reproduce the sponsor’s repeated-measures modeling. One recalculated comparison, between the two QVM149 groups, has an estimate of -0.021 L, a 95% interval from -0.057 to 0.015, and p = 0.248; it is not the sponsor’s primary lower-dose contrast.

The discrepancy flag is true. Accordingly, the sponsor’s own analysis takes precedence, and the recalculations should be treated as a separate, simpler reading of the posted summaries rather than as a correction or alternative primary result. The registry record does not report enough model detail to reconstruct the sponsor analysis independently.

15. Multiplicity, Missing Data and Analysis Populations

The registry record reports 24 outcome measures and 140 analyses, alongside multiple treatment groups, endpoints, and assessment times. It identifies two primary dose-pair comparisons and gives sponsor-reported p-values for them. However, a multiplicity procedure for the primary comparisons is not reported in the registry record. The record also does not state whether the secondary analyses were adjusted for multiplicity, whether a testing hierarchy was used, or which analyses were prespecified versus exploratory.

General statistical explanation: multiplicity arises when several hypotheses are tested. If each test is judged at the same nominal threshold without adjustment, the overall chance of at least one false-positive result can increase. Adjustment procedures or a prespecified hierarchy can control how evidence is interpreted across a family of tests. Without the plan, the reported p-values remain informative for their individual contrasts but cannot establish how the trial controlled error across all analyses.

The primary endpoint population is described as the full analysis set including participants with a valid measurement for that outcome. That description gives a broad analysis-population label, but the exact rules for inclusion, treatment of participants without valid Week 26 values, and handling of measurements after treatment discontinuation are not reported in the registry record. The registry record does not report the amount or pattern of missing primary endpoint data, the imputation method, or the missing-data assumptions used in the model.

General statistical explanation: repeated-measures models can use available measurements without requiring every participant to have a complete set of visits, but the validity of the resulting estimates depends on assumptions about why data are missing and on the model specification. The method name by itself does not establish those assumptions. The full statistical analysis plan, sensitivity analyses for missing data, and detailed analysis-population definitions are not reported in the registry record. These omissions limit independent assessment of robustness, especially across the broad set of posted outcomes.

16. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: asthma (2.4%), pneumonia (0.8%), lower respiratory tract infection (0.5%), pulmonary embolism (0.5%), cholelithiasis (0.5%).

Safety counts are reported separately from the primary endpoint analysis counts. In the QVM149 150/50/160 μg group, 46 of 616 participants at risk had a serious adverse event; in the QVM149 150/50/80 μg group, the corresponding counts are 49 of 617. For QMF149 150/320 μg, the counts are 52 of 613, and for QMF149 150/160 μg they are 38 of 608. In the salmeterol/fluticasone group, 39 of 618 participants at risk had a serious adverse event. The registry record also lists deaths by group: 2, 1, 4, 0, and 0, respectively.

Asthma is listed as a serious adverse event term at 2.4%, pneumonia at 0.8%, lower respiratory tract infection at 0.5%, pulmonary embolism at 0.5%, cholelithiasis at 0.5%, and myocardial infarction at 0.3%. These are posted event summaries. They do not, by themselves, establish whether an event was caused by a treatment, nor do the group counts alone account for exposure duration or differences in participant characteristics.

The registry record does not report the detailed definitions, adjudication process, event timing, or comparative statistical analysis for these safety results. Safety interpretation should therefore remain descriptive and limited to the recorded counts and terms.

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

The posted primary results describe differences in model-based Week 26 trough FEV1 between QVM149 and the corresponding QMF149 doses. For both intended dose pairs, the sponsor reports a positive contrast, a 95% confidence interval above zero, and p < 0.001. This supports a statistical distinction between the groups for this endpoint under the sponsor’s repeated-measures analysis.

That finding is specific to a spirometric measure, its measurement timing, and the participants included in the primary analysis. It does not by itself establish effects on every aspect of asthma control, symptoms, quality of life, or future health outcomes. It also does not show whether a difference meets a threshold that patients or clinicians would regard as important; a clinical-importance threshold is not reported in the registry record. No medical recommendation follows from the statistical comparison.

The trial included a salmeterol/fluticasone group, and secondary results include comparisons involving that group. Those results provide additional context but are not the primary dose-pair question. The registry record contains several outcomes and analyses, and the multiplicity strategy is not reported. Secondary tests therefore warrant more cautious interpretation than the designated primary analyses.

The safety summaries list serious adverse events and deaths in all treatment groups. These counts are descriptive and do not establish causation or a treatment-specific safety advantage. The registry record does not provide sufficient detail to assess event exposure time, adjudication, or adjusted safety contrasts.

Finally, the record’s limited reporting of eligibility details, missing-data methods, model specification, and the original design justification constrains independent evaluation. The findings should be understood as the results of the reported trial analyses, not as proof about unreported outcomes or populations.

18. Why This Trial Matters Statistically

This trial illustrates why the identity of the comparison matters as much as the endpoint estimate. The primary question pairs each QVM149 dose with a corresponding QMF149 dose, while the simple recalculations use one QVM149 group as a common reference. Those are different contrasts. Reading the recalculated comparison as though it were the sponsor’s primary comparison would lead to an incorrect interpretation of the lower-dose result. The discrepancy flag and the sponsor’s reported model-based analyses make that distinction especially important.

The trial also shows why an effect estimate should be read with its confidence interval and analysis method. The sponsor reports positive Week 26 contrasts with intervals above zero, while the arm summaries give the scale of the endpoint and its standard errors. Together, these quantities describe the estimated between-group differences and their precision under the reported analysis; a p-value alone would be less informative.

A further statistical issue is the breadth of the registry’s outcome and analysis record. Multiple endpoints, visits, and comparisons create a multiplicity question, yet the adjustment strategy is not reported. Secondary outcomes can help assess whether the primary pattern is accompanied by changes in related measures, but they do not automatically carry the same evidential status as a prespecified primary result.

Finally, the planning illustrations are useful for understanding how assumed effect size relates to participant requirements. They are not evidence about the trial’s original planning process or its achieved power. Distinguishing prospective planning calculations from observed results, and distinguishing model-based sponsor analyses from simple recalculations, are central to sound statistical reading of this record.

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 trial-specific reporting gaps limit independent assessment. The registry record does not provide detailed eligibility criteria, baseline participant characteristics, allocation procedures, or stratification factors. It identifies the study as randomized and parallel-group, but does not describe how the random sequence was generated or concealed. The official title calls the study double-blind, while the masking field specifies quadruple masking; the record does not explain that difference.

The sponsor’s primary analysis is identified as MMRM, but the full model specification is not reported. Details such as covariates, covariance structure, degrees-of-freedom method, and sensitivity analyses are not reported in the registry record. The record also does not report the original sample-size justification or the trial’s own design assumptions, so the planning illustrations cannot be used to reconstruct them.

The discrepancy flag indicates that the simple recalculations do not align with the sponsor-reported analyses. The recalculations use summary statistics, approximate standard deviations, and unadjusted comparisons; the sponsor reports model-based contrasts for the stated primary dose pairs. The sponsor analysis therefore takes precedence, while the discrepancy limits the usefulness of the recalculated comparisons as a check on the primary result.

For missing data, the amount, reasons, and pattern of missing primary measurements are not reported in the registry record. Nor are the model’s missing-data assumptions or sensitivity analyses reported. The record lists many outcomes and analyses, but does not report a multiplicity strategy. Safety summaries lack detailed event timing and comparative analysis. These limitations do not negate the posted results, but they restrict how completely readers can evaluate robustness, clinical importance, and the full range of potential bias.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Study to Compare the Efficacy and Safety of QVM149 With QMF149 in Patients With Asthma — NCT02571777.
• Registry record last updated 2020-07-22; status last verified 2020-07.
• Results first posted 2020-07-22.
• 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

NCT02571777 is a completed Phase 3 randomized parallel-group trial sponsored by Novartis Pharmaceuticals, with 3092 participants enrolled. It compared two once-daily QVM149 dose combinations with corresponding QMF149 doses and included a salmeterol/fluticasone group. The primary outcome was trough FEV1 at Week 26 in the full analysis set with a valid measurement.

The sponsor’s MMRM analyses report positive primary contrasts for both intended QVM149-versus-QMF149 dose pairs, each with a 95% confidence interval above zero and p < 0.001. The simple recalculations use different comparisons; because the discrepancy flag is true, the sponsor’s analyses take precedence. Secondary outcomes and descriptive safety counts add context, while missing details about multiplicity, model specification, missing data, and the original design assumptions limit independent assessment.