An 8-week Dose Ranging Study of CHF 718 pMDI in Asthmatic Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An 8-week Dose Ranging Study of CHF 718 pMDI in Asthmatic Subjects (NCT03084718), a randomized phase 2 study. The primary outcome is Pre-dose Morning FEV1 at Week 8 - Change From Baseline.

2. Clinical Question

The registry describes a randomized, double-blind, placebo- and active-controlled, parallel-group study. Its stated purpose was to evaluate lung function and other clinical outcomes across the tested doses. The primary endpoint provides a continuous measure of lung function, while the secondary outcomes include other lung-function measures, asthma control and symptoms, and rescue-medication use.

3. Trial Design

This was a Phase 2, randomized, quadruple-masked, parallel-group study in asthmatic subjects. The registry describes it as an eight-week, multicenter, double-blind study with placebo and active control. Enrollment was 610. The listed study dates are 2017-07-28 for study start and 2018-11-28 for primary completion; the status is completed.

Participants were assigned to one of five treatment groups: CHF 718 pMDI at 100 μg total daily dose, CHF 718 pMDI at 400 μg total daily dose, CHF 718 pMDI at 800 μg total daily dose, matched placebo pMDI, or beclomethasone dipropionate delivered as QVAR® at 320 μg total daily dose. The registry specifies twice-daily inhalation schedules for the listed treatments. The design therefore allows the reported results to be considered across dose levels and against placebo and an active comparator.

The primary endpoint was change from baseline in pre-dose morning FEV1 at Week 8. Secondary outcomes included pre-dose morning FEV1 at Week 4, FVC at Week 4 and Week 8, ACQ-7 scores, rescue-medication use, symptom scores, and percentages of rescue-medication-free, asthma-symptom-free, and asthma-control days. The registry lists 16 outcome measures and 168 analyses, and 15 secondary outcomes are posted.

The primary analysis population is defined as all randomized patients who received at least one dose of study treatment and had at least one available post-baseline efficacy evaluation for a primary or secondary efficacy variable. Further detail about recruitment procedures, the allocation sequence, concealment, or the operational meaning of quadruple masking 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intention to treat: All randomized patients who received at least one dose of the study treatment and with at least one available evaluation of efficacy after baseline (primary or secondary efficacy variables) after the baseline.

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: Demographic characteristics are presented for the Intention-to-treat (ITT) study population; this explains the differences in the randomized patient numbers that are shown in the Participant Flow.

6. Primary Endpoint

The registry lists the primary outcome as Pre-dose Morning FEV1 at Week 8 - Change From Baseline, measured over Baseline, Week 8.

The primary endpoint measures change from baseline in pre-dose morning forced expiratory volume in the first second, or FEV1, at Week 8. FEV1 is the volume of air exhaled during the first second of a forced expiratory manoeuvre. The endpoint is reported in litres, and the registry defines the baseline value as the average of pre-dose FEV1 measurements taken at V2 (Week 0), 45 minutes and 15 minutes before dosing. The Week 8 value is described as an average of pre-dose FEV1 measurements.

FEV1 is used as a continuous measure of lung function. A continuous endpoint retains the size and direction of measured changes rather than reducing results to categories. In this trial, the reported arm summaries are least-squares means with 95% confidence intervals. The registry says spirometry was performed according to internationally accepted standards.

Change from baseline frames the Week 8 measurement relative to each participant’s starting value, while the between-group analyses estimate differences between treatment groups. These are related but not identical summaries: the arm estimates describe change within each group, and the mixed-model comparisons report contrasts between groups. The endpoint is one part of the study’s assessment; secondary outcomes covered FVC, asthma control, symptoms, and rescue-medication use. The registry record does not report a clinically meaningful threshold for interpreting a given FEV1 change, so statistical estimates alone do not establish the clinical importance of a particular value.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports arm-level least-squares mean changes and mixed-model mean differences for a continuous endpoint. These summaries answer different questions. An arm mean describes the estimated average change from baseline within that group. A mean difference compares the estimated outcome between the named groups under the reported model. A difference estimate is accompanied by a confidence interval and p-value, which help describe the uncertainty and statistical evidence for that contrast.

What does a confidence interval convey?

A 95% confidence interval gives a range of values compatible with the data and the statistical procedure, under the model’s assumptions. It is not a guarantee that the true effect falls within the particular interval, nor does it show the range of individual participants’ responses. A narrower interval indicates greater precision than a wider interval. Whether an interval includes zero is relevant when the contrast is expressed as a difference: zero represents no difference on that scale. For example, the reported interval for Treatment B versus placebo is 0.018 to 0.209 litres, whereas the interval for Treatment C versus placebo is -0.003 to 0.188 litres. These intervals describe different degrees of uncertainty; neither interval alone determines clinical importance.

How should the p-values be read?

A p-value measures how incompatible the observed data are with a specified null hypothesis, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, and it is not a measure of effect size. The registry reports p=0.015 for Treatment B versus placebo and p=0.059 for Treatment C versus placebo. These values should be interpreted alongside the corresponding effect estimates and confidence intervals. The registry does not report whether the comparisons were adjusted for multiple testing, so the p-values cannot be assumed to account for the many outcomes and analyses listed in the record.

Why use a mixed model?

Mixed models can represent relationships among repeated measurements and can estimate treatment contrasts while accounting for features specified in the model. Their interpretation depends on the model terms, covariance structure, assumptions about missing observations, and analysis population. The registry identifies the method as “Mixed Models Analysis” but does not report the full model specification, covariates, handling of missing data, or sensitivity analyses. Those omissions limit independent assessment of the estimates’ assumptions. No further model details should be inferred from the method label alone.

What does least-squares mean mean?

A least-squares mean is a model-based estimate of an average. Depending on the model, it may be adjusted for included variables or other design features. It is not necessarily the same as a simple arithmetic average of observed measurements. The registry gives least-squares mean changes for each arm and separate mean differences for comparisons, but does not describe which adjustments produced the estimates. The arm values and the contrast values therefore should be kept distinct rather than treated as interchangeable summaries.

How does the design bear on interpretation?

Randomization, masking, and parallel groups are stated design features. In general, randomization aims to make assigned groups comparable at the start of a trial, while masking can reduce some forms of knowledge-related influence on care or assessment. These design features do not remove the need to examine attrition, adherence, missing measurements, outcome definitions, and analysis choices. The registry does not report detailed information on these matters. The primary analysis population requires receipt of at least one dose and an available post-baseline efficacy evaluation, so it is not described as every randomized participant regardless of treatment receipt or data availability.

The planning illustration is based on the observed effect and specified assumptions: a two-sided significance level of 0.05, equal allocation between arms, a normal approximation, and an effect to detect expressed as a fraction of the observed effect. Such illustrations are prospective planning calculations, not observed power and not evidence that the trial was designed with those assumptions. The registry record does not report the trial’s own sample-size justification. It also does not report interim analyses, a prespecified multiplicity strategy, or the full statistical analysis plan.

10. Analyses Reported by the Sponsor

The registry’s reported comparisons are sponsor analyses using mixed models, with the parameter described as mean difference in final values. For the primary endpoint, the record lists the comparison estimate, 95% confidence interval, and p-value for each reported contrast. These are the estimates to use when describing the sponsor’s own analysis.

No discrepancy is flagged between a recalculation and the sponsor’s analysis in the registry record. The posted comparisons should therefore be read as the principal reported inferential results, rather than replaced by an unadjusted reconstruction. A simple recalculation from summary statistics, if available, would not necessarily reproduce a mixed-model estimate: the model may incorporate information or assumptions not captured by the arm-level means and confidence intervals alone. The full specification needed to assess that distinction is not reported in the registry record.

The registry identifies the arm summaries as least-squares means and the comparisons as mean differences from a mixed-model analysis. It does not provide details sufficient to reconstruct those model-based estimates independently. Accordingly, the reported estimates can be described with their stated uncertainty, but the record does not support a claim that an unadjusted calculation would be equivalent to the sponsor’s analysis.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures, 168 analyses, and 15 posted secondary outcomes. The primary endpoint is change from baseline in pre-dose morning FEV1 at Week 8. The listed secondary outcomes cover lung function, asthma-control scores, symptoms, and rescue-medication use, with several measured at more than one time point. The record reports multiple pairwise comparisons for the primary endpoint as well.

When many outcomes or contrasts are examined, the chance of at least one apparently notable result can increase. Statistical methods can address this issue, but the registry record does not report a multiplicity-adjustment plan or identify which results, if any, were adjusted. It is therefore not possible to determine from the record whether the reported p-values are unadjusted, adjusted, or part of a prespecified testing hierarchy. The reported p-values should be read as posted, without assuming a particular correction.

The primary analysis population is defined as randomized patients who received at least one dose and had at least one available post-baseline efficacy evaluation for a primary or secondary efficacy variable. This definition excludes randomized participants who did not satisfy those conditions from the stated population. Arm-level endpoint counts are reported, but the reasons for any differences between those counts and other enrollment figures are not given. The handling of missing endpoint measurements, including imputation or model assumptions, is not reported in the registry record.

The registry does not report the full statistical analysis plan, a sample-size justification, interim-analysis procedures, or sensitivity analyses for missing data. The planning illustration uses stated assumptions and the observed effect; it is not a substitute for the trial’s own design rationale. These omissions matter when considering how robust the estimates are to analysis choices and how the primary result relates to the wider set of outcomes.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lower limb fracture (0.8%), alcohol poisoning (0.8%), diplopia (0.8%), diverticulitis (0.8%), chest pain (0.8%).

The registry reports serious adverse events and other adverse-event counts by treatment group. Serious adverse events were reported for 1 participant in Treatment A, 2 in Treatment B, 2 in Treatment C, 1 in placebo, and 0 in QVAR®. The corresponding serious-event groups at risk were 119, 120, 121, 124, and 124. These are counts in the posted record; they do not by themselves describe the timing, duration, or causal relation of events to treatment.

The record lists one death in Treatment B and none in the other groups. It does not provide a cause of death in the registry record for this account. Serious-event terms listed at 0.8% each are lower limb fracture, alcohol poisoning, diplopia, diverticulitis, chest pain, and multiple injuries. Each listed term should be understood as a registry-reported event category, not as an estimate of comparative risk.

Other adverse-event counts were 18 in Treatment A, 8 in Treatment B, 25 in Treatment C, 28 in placebo, and 21 in QVAR®. The registry gives the number at risk for these counts as 119, 120, 121, 124, and 124, respectively. Differences in event counts do not establish treatment causation or comparative safety. The registry record does not report further context about severity, exposure time, event ascertainment, or statistical comparisons for these safety figures.

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

The primary endpoint provides a statistical comparison of change in pre-dose morning FEV1 at Week 8 across the randomized groups. The posted arm estimates and mixed-model contrasts indicate the values observed under the registry’s stated analysis. For Treatment B versus placebo, the reported mean difference was 0.113 litres with a 95% confidence interval from 0.018 to 0.209 and p=0.015. For Treatment C versus placebo, the estimate was 0.093 litres, with a 95% confidence interval from -0.003 to 0.188 and p=0.059. The other listed contrasts also have their own estimates and uncertainty, which should be considered rather than relying on a single p-value.

These results do not establish how important a given change is to patients. A clinical interpretation would require a meaningful-change threshold and context about symptoms and other outcomes; such a threshold is not reported in the registry record. Nor do the estimates describe the experience of every participant. They are group-level statistical summaries for the stated analysis population.

The results also do not establish a simple dose-response pattern. The reported arm mean changes for the three CHF 718 doses are 0.021 litres, 0.09 litres, and 0.07 litres. The 400 μg group has a larger posted mean change than the 800 μg group, and the direct comparison between those groups has a confidence interval from -0.101 to 0.059 with p=0.612. This is a description of the reported estimates, not proof that the doses are equivalent or that a dose-response relationship is absent.

The registry’s purpose includes safety and other clinical outcomes, but the primary endpoint alone cannot answer those broader questions. Interpretation is further limited by unreported multiplicity procedures, missing-data methods, model details, and a clinical threshold for meaningful change. The statistical results should therefore be read as estimates with uncertainty within the reported trial, rather than as a stand-alone conclusion about treatment benefit or safety.

14. Why This Trial Matters Statistically

This trial illustrates why a dose-ranging study needs more than a comparison of each treatment group’s mean change. The arm estimates describe the average change within each group, while the between-group contrasts address whether estimated outcomes differ across groups. Their confidence intervals show how precisely those contrasts are estimated. Looking at both avoids treating an arm’s within-group change as though it were itself a randomized comparison.

The dose pattern also demonstrates why numerical ordering is not enough to establish a dose-response relationship. The reported changes for CHF 718 pMDI are not progressively larger across the listed doses, and the direct comparisons among those groups have confidence intervals that include zero. A dose-ranging objective can motivate examining such patterns, but the registry’s results need to be interpreted in light of uncertainty and the unreported modeling and multiplicity details.

The presence of placebo and active controls adds useful comparative context. The registry reports contrasts against placebo and a comparison of placebo with QVAR®, alongside the CHF 718 dose comparisons. These analyses address distinct questions and should not be collapsed into a single claim. The secondary outcomes broaden the assessment beyond FEV1 to asthma control, symptoms, rescue medication, and FVC, but the record does not report a multiplicity strategy for the many analyses.

Finally, the record distinguishes posted estimates from what they can establish. Confidence intervals and p-values quantify aspects of statistical uncertainty; they do not determine clinical importance, individual response, or unreported safety context. This makes the trial a useful example of reading effect estimates, comparison structure, and uncertainty together, while keeping the limits of registry reporting in view.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record does not report the full mixed-model specification, including covariates, covariance structure, or other modeling choices. It identifies the comparison method and parameter, but these labels do not provide enough detail to reproduce the model-based estimates independently or judge all of its assumptions.

Missing-data handling is also not reported. The primary analysis population requires at least one dose and at least one available post-baseline efficacy evaluation. The record does not explain the reasons for unavailable measurements, describe imputation, or provide sensitivity analyses. This makes it difficult to assess how departures from complete follow-up might affect the estimates.

Multiplicity is a specific concern because the record lists 16 outcome measures, 168 analyses, and 15 posted secondary outcomes. The registry does not state whether p-values were adjusted or how primary and secondary hypotheses were organized. The meaning of individual p-values across this set of analyses is therefore uncertain with respect to family-wise or other multiplicity control.

The endpoint is reported in litres, but a clinically meaningful threshold for FEV1 change is not reported. Consequently, the statistical magnitude cannot be translated from the registry record alone into a judgment about clinical importance. The eight-week study duration also means the posted primary endpoint concerns the specified Week 8 assessment; longer-term outcomes are not addressed by that endpoint.

Safety interpretation is limited by the event counts and terms reported. Additional information about event timing, severity, exposure, and causality is not reported in the registry record. The record also does not report its own sample-size justification, interim analyses, or further recruitment and allocation procedures. These limitations do not negate the posted estimates, but they constrain how completely their precision, robustness, and broader relevance can be evaluated.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An 8-week Dose Ranging Study of CHF 718 pMDI in Asthmatic Subjects — NCT03084718.
• Registry record last updated 2021-12-14; status last verified 2021-12.
• Results first posted 2021-12-14.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT03084718 is a completed Phase 2 randomized, quadruple-masked, parallel-group dose-ranging study of CHF 718 pMDI in asthmatic subjects. It enrolled 610 participants and included CHF 718 pMDI at 100 μg, 400 μg, and 800 μg total daily dose, matched placebo, and QVAR® at 320 μg total daily dose.

The primary endpoint was change from baseline in pre-dose morning FEV1 at Week 8, reported as a least-squares mean in litres with a 95% confidence interval. The registry reports arm estimates and mixed-model comparisons, alongside secondary outcomes covering lung function, asthma control, symptoms, and rescue-medication use. Statistical interpretation is constrained by registry entries not reported for model specification, multiplicity, and missing-data handling, as well as the absence of a reported clinical-importance threshold.