A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis (NCT03911713), a randomized phase 2 study. The primary outcome is Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1).

2. Clinical Question

This question concerns a measured change in lung function over the treatment period, not a direct measure of how participants felt or functioned in daily life. The registry also lists secondary outcomes: absolute change in sweat chloride, observed pre-dose concentrations of VX-561 and its metabolites and IVA and its metabolites, and safety and tolerability assessed through treatment-emergent adverse events and serious adverse events. These outcomes address different aspects of pharmacodynamic response, drug exposure and safety. Their inclusion does not make them interchangeable with the primary lung-function endpoint.

3. Trial Design

The registry describes a randomized, parallel-group phase 2 study. Its official title calls it double-blind, while the registry's masking classification is quadruple. The record does not explain which people or roles were masked, or how masking was maintained. The study is listed as completed, with enrollment of 77. Its recorded start date is 2019-04-17 and its primary completion date is 2020-08-20.

The treatment groups described in the record were ivacaftor and four VX-561 dose levels. Ivacaftor was taken orally at 150 mg every 12 hours; VX-561 was taken orally once daily at 25 mg, 50 mg, 150 mg or 250 mg. Each arm description gives a 12-week treatment period. Although placebo appears in the intervention list, the posted primary results identify ivacaftor as the control and give estimates for the 150 mg and 250 mg VX-561 arms. The registry record does not describe a placebo group among the primary endpoint results.

The 25 mg and 50 mg VX-561 arms were discontinued at the sponsor's discretion. Their primary endpoint values are not reported in the posted results. The record's primary-population description says the Full Analysis Set included randomized participants with the intended CFTR genotype who received at least 1 dose during the treatment period. The text describing this population is incomplete after noting the discontinued arms, so further details about how those arms were handled in the primary analysis are not reported in the registry record.

The record lists four outcome measures, while three secondary outcomes are described. It reports 0 analyses. This means the registry entry does not provide a set of formal analysis details for interpreting the posted endpoint estimates. In particular, the exact randomization procedure, allocation concealment, protocol-level sample-size justification, and detailed statistical analysis plan are not reported in the registry record. The design labels and arm descriptions establish the broad structure and treatment schedule, but do not fill in those methodological details.

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: This study was conducted in cystic fibrosis (CF) participants aged 18 years or older who have a gating mutation and were previously taking stable dose of ivacaftor (IVA).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) included all randomized participants who have intended CF transmembrane conductance regulator gene (CFTR) genotype and received at least 1 dose of study drug in treatment period. VX-561:25 mg and VX-561:50 mg arms were discontinued at sponsor's discretion and it was specified in statistical plan that data will be reported for only IVA, VX-561:150 mg and VX-561:250 mg arms for this 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.

6. Primary Endpoint

The registry lists the primary outcome as Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1), measured over From Baseline at Week 12.

The primary endpoint is absolute change from baseline at Week 12 in percent predicted forced expiratory volume in 1 second, abbreviated ppFEV1. FEV1 is the volume of air that can forcibly be blown out in one second after full inspiration. The percent-predicted scale expresses lung function relative to a predicted value; the endpoint is reported in percentage points. The registry identifies the reported measure as a least-squares mean and gives a 95% confidence interval for each posted group estimate.

Change from baseline focuses on how the measured value at follow-up differs from the participant's starting value. A group mean summarizes the average change across the participants included in that analysis, while the confidence interval conveys uncertainty around the estimated mean. These are general statistical interpretations; they do not establish the clinical importance of a particular change. The registry record does not provide a threshold for a clinically meaningful difference.

FEV1 is used as a lung-function measure because it quantifies the volume expelled during a defined breathing maneuver. The use of a percent-predicted scale can help describe lung function in relation to a reference expectation, while change from baseline focuses on movement during the study period. These are general reasons for using such a measure. The posted endpoint is not itself a direct measure of symptoms, quality of life, or long-term outcomes.

The available estimates concern three groups: ivacaftor, VX-561 150 mg and VX-561 250 mg. The registry does not post a direct between-group estimate for VX-561 versus ivacaftor. Therefore, the group-specific changes should not be read as if they were treatment differences. A contrast between groups requires an estimate of the difference and its uncertainty, which is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: it is a measured change in ppFEV1, reported in percentage points. The registry identifies the summary as a least-squares mean and the uncertainty measure as a 95% confidence interval. The following explanations are general statistical concepts, not additional details of the study's analysis plan. The registry record does not report the full model specification used to obtain these estimates.

What does a least-squares mean represent?

A least-squares mean is a model-based estimate of a group mean. In a trial analysis, a statistical model may account for features such as baseline measurements or other prespecified variables. The resulting estimate can differ from a simple arithmetic average if the model includes adjustments. Because the registry does not report the model terms, covariates, or estimation details, the posted least-squares means should be described by their stated label rather than treated as raw averages. The record does not report enough information to reproduce the estimates independently.

How should a confidence interval be read?

A confidence interval describes uncertainty in an estimated quantity under the assumptions of the analysis. In general, a 95% confidence interval is produced by a procedure that would cover the true quantity in 95% of repeated samples if the model assumptions and sampling process were appropriate. It is not a probability statement that the particular true value has a 95% chance of being inside the observed interval. It also does not describe the range of individual participants' outcomes.

For these group-specific mean changes, the interval gives a range of values compatible with the data and the stated procedure. Every posted interval includes zero, so a zero mean change is among the values compatible with each interval. The interval also permits nonzero changes in either direction. This general interpretation does not imply that every value in the interval is equally plausible, nor does it establish equivalence between groups. An equivalence conclusion would require an appropriate design, a prespecified equivalence margin, and a suitable comparison; these details are not reported in the registry record.

Why distinguish a group estimate from a treatment contrast?

A group-specific change asks how the measured endpoint changed from baseline in that group. A treatment contrast asks how much the change differed between groups. These are different estimands. A treatment contrast is usually obtained by directly comparing the groups in a model, with its own uncertainty interval and inferential result. The registry lists a control group, but the posted primary results give separate least-squares means and confidence intervals rather than a VX-561-versus-ivacaftor contrast. Subtracting the reported point estimates would be a new calculation and would not reproduce a model-based comparison. No such contrast is reported in the registry record.

What does the analysis population tell the reader?

The stated Full Analysis Set included all randomized participants who had the intended CFTR genotype and received at least 1 dose of study drug in the treatment period. This definition indicates that randomization alone was not the only stated membership condition. The record does not give a complete account of exclusions, the number of participants in the primary analysis for each group beyond the posted group counts, or the handling of participants without a Week 12 measurement. The arm counts accompanying the endpoint estimates are 11 for ivacaftor, 23 for VX-561 150 mg and 24 for VX-561 250 mg.

In general, analysis-population definitions matter because they determine which participants contribute to an estimate. An analysis that includes all randomized participants, an analysis limited to those who received treatment, and an analysis limited to those with a measured endpoint can produce different results. These are general possibilities, not a description of analyses performed in this study. The registry's population description and outcome counts do not establish which additional analyses were conducted.

What can be inferred from the reported sample sizes?

The group counts indicate the number of participants associated with the posted estimates, but they do not by themselves show the precision that would have been achieved under a different design or sample size. Smaller groups generally provide less information about a mean than larger groups when other factors are comparable; that is a general statistical principle. The observed confidence intervals are the reported indication of uncertainty for these estimates. The registry does not report a protocol-level sample-size justification or a target effect used to plan enrollment.

The stated planning assumptions for the separate sample-size illustrations use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Those are planning assumptions, not observed results or evidence of the study's original design. The registry does not report the fraction values or a trial-specific sample-size rationale. A planning calculation cannot establish the probability that this completed study detected an effect, and it should not be described as observed power.

Why might variability affect the interpretation?

For continuous outcomes, the spread of participant measurements affects the uncertainty of a mean and the precision of a treatment contrast. Greater variability generally makes estimates less precise when other features are alike. This is a general explanation. The registry does not report a standard deviation or another participant-level measure of spread for the primary outcome; it reports confidence intervals around the least-squares means. Those intervals, not an assumed variability value, are the posted uncertainty summaries.

More generally, a model's assumptions and the pattern of missing measurements can affect estimates. If variability differs across groups or measurements are missing for reasons related to outcomes, a simple analysis may not adequately describe uncertainty or bias. This is general context only: the registry record does not report diagnostic checks, an approach to missing primary endpoint values, or sensitivity analyses. It also does not report interim analyses, adjustment for multiple testing, or a full statistical analysis plan. Those features should not be inferred from the fact that the study was randomized or masked.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is one measure, but the record also lists secondary outcomes covering sweat chloride, pre-dose concentrations of VX-561 and metabolites and of IVA and metabolites, and safety and tolerability. It reports four outcome measures and describes three secondary outcomes. The registry record does not report how the study handled the possibility of multiple statistical tests across outcomes, doses, time points, or comparisons. It is therefore not possible to determine whether a multiplicity adjustment was planned or applied, or how any secondary findings should be interpreted in light of multiple testing.

The registry lists 0 analyses. It does not report a detailed statistical analysis plan, interim analyses, or inferential results for the secondary outcomes. The listed outcomes identify what was assessed, but do not establish the analysis methods or the availability of results for each measure. Those details are not reported in the registry record.

The stated primary population included randomized participants with the intended CFTR genotype who received at least 1 dose of study drug. The record does not describe how missing Week 12 ppFEV1 values were handled, whether participants with incomplete measurements were excluded, or whether any imputation or sensitivity analysis was used. It also does not give reasons for missing endpoint data or describe how discontinuation of the 25 mg and 50 mg arms affected follow-up and analysis. These omissions limit assessment of whether the endpoint estimates could be affected by missingness or changes to the planned treatment groups.

The distinction between the stated population and the participants contributing data matters. A population definition indicates intended eligibility for an analysis, but does not show how many participants had usable measurements or how missing values were treated. The posted group sizes accompany the estimates, but further detail on participant flow and endpoint availability is not reported in the registry record. No assumptions about missing data or multiplicity should be inferred from the reported confidence intervals alone.

11. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: infective pulmonary exacerbation of cystic fibrosis (18.2%), distal intestinal obstruction syndrome (16.7%), forced expiratory volume decreased (16.7%).

The safety results count participants with serious adverse events and with other treatment-emergent adverse events in each listed group. For serious adverse events, the counts were 1 of 11 in the ivacaftor group, 2 of 6 in the VX-561 25 mg group, 2 of 11 in the VX-561 50 mg group, 2 of 23 in the VX-561 150 mg group, and 1 of 24 in the VX-561 250 mg group. The registry reports 0 deaths in each of these groups.

For other treatment-emergent adverse events, the counts were 8 of 11 for ivacaftor, 4 of 6 for VX-561 25 mg, 8 of 11 for VX-561 50 mg, 17 of 23 for VX-561 150 mg, and 20 of 24 for VX-561 250 mg. These are participant counts, not estimates of comparative risk. Group sizes differ, and the registry does not report a formal statistical comparison of adverse-event rates.

Counts of participants with an event do not describe the number, duration, severity, or relatedness of every event, and they do not establish that treatment caused an event. The record lists infective pulmonary exacerbation of cystic fibrosis, distal intestinal obstruction syndrome, and forced expiratory volume decreased among top serious-event terms, but does not provide enough context in these results to connect those terms to a particular group or make a causal interpretation. The short treatment period and the posted counts also cannot establish the frequency of events beyond the study's observed follow-up.

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

The primary results describe estimated average change in ppFEV1 from baseline to Week 12 for three groups. The ivacaftor estimate was -0.8 percentage points; the VX-561 150 mg estimate was 3.1 percentage points; and the VX-561 250 mg estimate was 2.7 percentage points. Each estimate has a 95% confidence interval that includes zero. These figures convey the direction and uncertainty of each group-specific mean change, within the limits of the reported analysis.

They do not directly quantify the difference between VX-561 and ivacaftor. The registry record does not report a treatment contrast, p-value, or confidence interval for a contrast. Separate group estimates cannot establish whether one treatment produced a larger change than another. Nor do these results establish whether a change is clinically important: a threshold for meaningful change is not reported in the registry record.

The results also do not support a complete dose-response interpretation. Primary endpoint estimates are posted for two VX-561 doses, while the 25 mg and 50 mg arms were discontinued at the sponsor's discretion and their endpoint values are not reported. The reason for the discontinuation and its effect on the interpretation of the available groups are not reported. No conclusion about all planned dose levels follows from the posted values for the two higher-dose groups.

The primary endpoint captures a specific lung-function measure over a 12-week treatment period. It does not answer whether any change lasted after treatment, whether symptoms or quality of life changed, or what longer-term outcomes occurred. The registry lists secondary measures related to sweat chloride, drug concentrations and safety, but the information available for this study does not provide their numerical findings or analysis details. Those questions remain distinct from the primary endpoint.

Finally, a completed randomized trial does not guarantee that every planned comparison or methodological detail is available in the registry record. The entry reports 0 analyses and does not provide the full statistical analysis plan, missing-data methods, multiplicity strategy, or trial-specific sample-size justification. The most defensible reading is therefore descriptive: consider the stated group estimates, their confidence intervals, and the limitations of the record, without treating them as proof of a treatment effect, absence of effect, or equivalence.

13. Why This Trial Matters Statistically

This study is a useful example of the distinction between reporting a group mean change and reporting a randomized treatment comparison. The primary outcome estimates are least-squares mean changes within each group, each with a confidence interval. Although the trial is randomized and identifies ivacaftor as the control, the registry does not provide the corresponding between-group effect estimate. Readers need that distinction to avoid interpreting a difference between two separately reported means as though it were an analyzed treatment contrast.

The confidence intervals also make uncertainty visible. Each includes zero, so the point estimates should not be read in isolation as definitive evidence of change. At the same time, intervals including zero are not proof that no effect exists. They reflect the range of values compatible with the data under the stated procedure, and the registry does not provide a contrast interval or p-value to answer the comparative question directly.

The record also illustrates why analysis populations and changes to trial arms matter. The primary population has a stated treatment-exposure criterion, and two VX-561 dose arms were discontinued at the sponsor's discretion. Primary endpoint estimates are available for only three groups. Without a complete account of participant flow, missing endpoint data, and the analysis plan, readers cannot fully assess how these features shaped the estimates.

Finally, the study highlights the difference between planning calculations and trial results. The recorded sample-size assumptions describe illustrations based on fractions of an observed effect; they are not the original design justification or evidence of observed power. Keeping those planning concepts separate from the endpoint estimates is important for sound interpretation. These are general statistical lessons illustrated by the information reported for this study.

14. 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 entry does not provide a direct VX-561-versus-ivacaftor estimate for the primary endpoint, or a p-value or confidence interval for that comparison. It reports group-specific least-squares means and confidence intervals, which do not alone establish a comparative treatment effect. The statistical model used to generate the estimates is not described in enough detail to assess or reproduce it.

The primary-population description is incomplete after noting that the 25 mg and 50 mg arms were discontinued at the sponsor's discretion. The record does not explain why those arms were discontinued, when the decision occurred, or how the change affected endpoint follow-up and analysis. It also does not report missing-data methods, sensitivity analyses, participant flow for the primary endpoint, or the number with a Week 12 measurement in each group.

The entry reports 0 analyses and does not give a complete statistical analysis plan, multiplicity approach, or trial-specific sample-size justification. The masking classification is quadruple, while the official title says double-blind; the record does not explain the roles covered by masking. Placebo appears in the intervention list, but the posted primary results identify ivacaftor as control and provide estimates for three groups. The record does not clarify the relationship between the listed placebo intervention and the posted primary results.

Only a 12-week treatment-period endpoint is described. Longer-term outcomes are not reported in the registry record. Although secondary outcomes are listed, numerical findings and inferential analyses for them are not included in the information available for this study. These limitations constrain both clinical and statistical interpretation and make it inappropriate to infer unreported design or analysis details.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Phase 2 Study to Evaluate Efficacy and Safety of VX-561 in Subjects Aged 18 Years and Older With Cystic Fibrosis — NCT03911713.
• Registry record last updated 2022-01-25; status last verified 2021-12.
• Results first posted 2022-01-25.
• 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.

18. Record Summary

This completed phase 2 study, NCT03911713, evaluated VX-561 in adults aged 18 years and older with cystic fibrosis. The registry describes a randomized, parallel-group design and lists quadruple masking; the official title describes the study as double-blind. Enrollment was 77. The recorded study start was 2019-04-17 and primary completion was 2020-08-20.

The primary endpoint was absolute change from baseline at Week 12 in ppFEV1, reported as a least-squares mean with a 95% confidence interval. Estimates are posted for ivacaftor, VX-561 150 mg and VX-561 250 mg. The VX-561 25 mg and 50 mg arms were discontinued at the sponsor's discretion, and their primary endpoint values are not reported. The record also lists secondary outcomes concerning sweat chloride, drug concentrations, and safety and tolerability.

The group-specific primary estimates have confidence intervals that include zero. A direct treatment contrast and detailed analysis methods are not reported in the registry record, so the posted estimates do not establish comparative efficacy. The safety results report serious and other treatment-emergent adverse-event counts and 0 deaths in each listed group. Interpretation is limited by the absence of a full statistical analysis plan, missing-data details, and a trial-specific sample-size justification.