A Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy (NCT03525574), a na phase 3 study. The primary outcome is Treatment Period: Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs).

2. Clinical Question

The study’s main question is about safety and tolerability during long-term treatment, rather than a randomized estimate of treatment effect. The registry also names efficacy outcomes, including changes in percent predicted forced expiratory volume in 1 second (ppFEV1), changes in sweat chloride, pulmonary exacerbations, and time to first pulmonary exacerbation. However, efficacy results are not reported in the registry record.

Because this is an open-label, single-group study, its event counts describe what was recorded among treated participants. They do not show how those counts compare with what would have occurred without the study treatment or with another assigned treatment. The extension group consists of participants from certain countries who continued into an extension period; the record does not establish it as a comparable control group.

3. Trial Design

This was a Phase 3, open-label, single-group study of VX-445 combination therapy in people with cystic fibrosis who were homozygous or heterozygous for the F508del mutation. The registry lists enrollment of 507 participants and reports the study as completed. The recorded start date is 2018-10-09, and the primary completion date is 2023-01-09.

The treatment-period regimen was ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours, for 192 weeks. The registry describes an extension period for participants from certain countries. The available extension description is incomplete, so its full treatment details are not reported in the registry record. The intervention list also includes IVA, but there is no randomized comparison described.

Open-label means that treatment assignment was not masked. A single-group design can describe outcomes among people who receive the intervention, but it does not provide the direct treatment contrast that random assignment to a concurrent control group can support. The registry explicitly notes that this is not a randomized comparison and that the arms are not a like-for-like control comparison.

The primary outcome concerns counts of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) during the treatment period, from Day 1 up to Week 196. The primary safety population included all participants who received at least one dose of study drug. Named secondary outcomes cover lung function, sweat chloride, pulmonary exacerbations, and time to first pulmonary exacerbation. Their numerical results and the detailed statistical plan are not reported in the registry record.

The registry does not report a sample-size justification, interim-analysis plan, or full protocol-level analysis plan. Those details should not be inferred from the enrollment or from the observed event counts.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total 507 participants were enrolled in this study from the parent studies VX17-445-102 (NCT03525444) and VX17-445-103 (NCT03525548). One participant was enrolled but did not receive any dose in this study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Open-Label Safety Set (OL-SS) included all participants who had received at least 1 dose of study drug in this open label study.

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: All participants who received at least one dose of the study drug in this open label study were included in the baseline characteristics.

6. Primary Endpoint

The registry lists the primary outcome as Treatment Period: Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs), measured over From Day 1 up to Week 196.

The primary endpoint counts participants with treatment-emergent adverse events and serious adverse events during the treatment period, from Day 1 up to Week 196. The Open-Label Safety Set includes participants who received at least one dose of study drug. The registry reports the event counts separately for the treatment and extension periods.

Counting affected participants is a direct way to describe how many people in the safety population experienced events during follow-up. It is useful for summarizing the observed safety experience in a treated group. A participant count does not, by itself, describe the total number of event episodes, their duration, or their severity beyond the distinction between serious and other events. The endpoint title includes TEAEs and SAEs; the record’s serious-event listings provide additional detail on the kinds of serious events recorded.

These are descriptive safety measures in an open-label, single-group study. Without a randomized control group, the counts do not estimate how many events were caused by treatment or how the event frequency differs from another treatment. The registry record does not report an adjusted comparison or a causal analysis. The endpoint is therefore best read as a record of events among participants observed during the specified periods, with its interpretation limited by the design and the information recorded.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry’s primary safety endpoint is a participant count, not a continuous measurement or a time-to-event estimate. Its focus is whether participants experienced treatment-emergent adverse events and serious adverse events during a stated period. The Open-Label Safety Set comprises those who received at least one dose of study drug. This population definition sets the group to which the primary safety counts refer.

What do participant counts describe?

A participant count records how many people in a defined group experienced an event. It is distinct from an event count: a person can experience repeated events, but a count of participants with an event does not enumerate every episode. It is also distinct from an event rate, which requires an explicit denominator and, for a person-time rate, a measure of time at risk. The reported safety figures are counts among participants at risk; they should not be converted into additional percentages or rates without the relevant analysis details.

In general, the denominator matters because a count can be interpreted only in relation to the population in which it was observed. Follow-up time and how participants enter or leave a period also matter. The registry supplies at-risk counts for the treatment and extension periods, but does not report a randomized comparison between them. The extension group’s different size and its description as participants from certain countries mean its figures are not a control benchmark for the treatment period.

What does an open-label, single-group design imply?

In an open-label study, treatment is not masked. In a single-group design, there is no randomized concurrent control group to provide a direct contrast. The observed adverse-event counts can describe the experience of participants receiving study treatment, but cannot separate treatment effects from the underlying disease, other circumstances, or the process of observing and reporting events. That limitation does not make the counts uninformative; it defines the question they answer.

Randomization, when used, can help balance both measured and unmeasured factors across comparison groups. Without it, differences between groups may reflect who entered each group, their follow-up, or other factors, rather than treatment. Here, the record itself cautions against treating the extension-period group as a like-for-like control. No comparative effect estimate is reported in the registry record.

How should serious events and uncertainty be read?

Serious adverse events are reported separately from other treatment-emergent adverse events. Seriousness is a classification of an event, not a statement about its cause. An event occurring after treatment begins is not, on that fact alone, established as caused by treatment. The record lists selected serious-event terms and percentages, but does not report attribution details or confidence intervals for the counts. General statistical interpretation therefore distinguishes observed frequency from causal attribution and from precision.

A confidence interval, in general, describes the range of values compatible with an estimate under a statistical model and its assumptions. It helps readers assess how precisely an estimate is determined. No confidence intervals for the primary safety counts are reported in the registry record, so the available summaries do not quantify uncertainty in that way. The absence of an interval is not evidence that the observed count is exact as an estimate of a broader population experience.

What can planning illustrations tell readers?

General sample-size planning asks how many participants might be needed to detect a specified effect under stated assumptions. The registry’s planning-illustration description refers to a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect defined as a stated fraction of the observed effect. Such an illustration is not the trial’s own design justification, and its sample sizes are planning illustrations, not observed power. No numerical planning results or trial-specific sample-size justification are reported in the registry record.

Observed power is not a substitute for uncertainty around a result. After data are collected, the observed estimate and its uncertainty are more informative than a power calculation based on the observed effect. For this study, the primary safety information is reported as counts, and no such power conclusion should be drawn from those counts. The registry record does not report the detailed statistical procedures used for all outcomes.

Why can over-dispersion matter?

General count-data methods sometimes assume that variability follows a particular distribution. Over-dispersion occurs when the observed variability exceeds that assumption. If it is ignored, standard errors and uncertainty estimates may be too small, making results appear more precise than warranted. This concept is relevant to analyses of event counts, but the primary endpoint is a count of participants with events, and the registry record does not report a model for this endpoint or an assessment of over-dispersion. It would therefore be inappropriate to claim that a particular count model or correction was used.

Overall, the methods that can be established from the registry are the endpoint definition, the safety population, the follow-up period, the open-label single-group design, and the reported counts. Further details, including the statistical plan and uncertainty estimates, are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures and names secondary outcomes involving ppFEV1, sweat chloride, pulmonary exacerbations, and time to first pulmonary exacerbation. It reports zero analyses in the registry record. Numerical secondary-outcome findings, a hierarchy of hypotheses, and a strategy for handling multiple comparisons are not reported in the registry record.

Multiplicity arises when several outcomes or comparisons are examined. In general, testing many hypotheses can increase the chance of at least one apparently notable result arising by chance. Statistical plans may address this through prespecified primary outcomes, hierarchical testing, or adjustment procedures, but the record does not state whether any such approach was used. It would be inappropriate to infer a multiplicity procedure from the number or names of outcomes alone.

Missing-data methods are also not reported in the registry record. The available description of the safety population says participants were included if they received at least one dose, but does not explain how incomplete follow-up, withdrawal, or missing event information was handled. These omissions limit assessment of whether all participants contributed comparable observation time and how missing information might affect estimates.

The registry does not report the detailed analysis populations for the named secondary outcomes, the statistical methods for those outcomes, or sensitivity analyses for missing data. These details matter because different outcome populations and missing-data assumptions can change the interpretation of estimates. The primary safety counts can be read as the recorded event experience in the stated safety population; broader claims about efficacy, multiplicity-adjusted inference, or the influence of missing data are not supported by the record.

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 (16.4%), haemoptysis (2.2%), distal intestinal obstruction syndrome (1.8%), influenza (1.4%), constipation (1.2%).

For the treatment period, 175 of 506 participants at risk had serious adverse events, and 501 of 506 had other treatment-emergent adverse events. The registry reports one death. In the extension period, no serious adverse events were reported among 11 participants at risk; other adverse events were reported among 7 of 11, with no deaths. The extension group is substantially smaller and is not a randomized control group.

The listed serious-event terms include infective pulmonary exacerbation of cystic fibrosis (16.4%), haemoptysis (2.2%), distal intestinal obstruction syndrome (1.8%), influenza (1.4%), constipation (1.2%), and pneumonia (1.2%). These are registry-listed percentages, not comparative estimates. The record does not report enough detail to establish their denominator, individual event histories, or causal attribution.

Seriousness does not itself establish that an event was caused by treatment. These figures describe events recorded during the study periods; they do not estimate excess events relative to another treatment or no treatment. The registry record does not report confidence intervals for these counts.

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

The posted results establish a descriptive safety picture for the participants included in the stated periods. During treatment, the registry records serious adverse events in 175 of 506 participants at risk and other treatment-emergent adverse events in 501 of 506. It also records one death. The extension-period counts are based on 11 participants at risk, with no serious adverse events and no deaths reported, and other adverse events in 7 participants.

These observations do not establish that treatment caused any particular event. They also do not estimate how event counts would differ under another treatment or without treatment, because the study was open-label and single-group rather than a randomized comparison. The extension participants do not provide a like-for-like control group. The size of the group and the absence of reported confidence intervals also limit conclusions about precision.

The registry names efficacy outcomes, including lung function, sweat chloride, and pulmonary exacerbations, but numerical efficacy results are not reported in the registry record. Safety counts cannot stand in for those outcomes or establish efficacy. Likewise, the title’s reference to long-term safety and efficacy is not itself a numerical finding.

In general, interpreting a study means matching a conclusion to the design, population, outcome, and follow-up that generated the data. Here, the event counts support statements about what was recorded among the participants at risk in each period. They do not support a causal treatment effect, a comparative safety claim, or an inference about outcomes not numerically reported. The appropriate reading is therefore bounded and descriptive, rather than a judgment that the treatment does or does not work.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between describing an observed safety experience and estimating a comparative treatment effect. Its primary endpoint counts participants with TEAEs and SAEs, making the population and follow-up period central to interpretation. The registry defines the safety population as participants who received at least one dose and specifies follow-up from Day 1 up to Week 196.

The study’s open-label, single-group design shapes what can be learned. A large collection of safety observations can characterize events recorded during treatment, but without a randomized control group it cannot isolate the contribution of treatment from other causes. This is why event counts should not be converted into causal claims simply because events occurred after treatment started.

The extension period highlights another statistical issue: group comparability. Its 11 participants at risk are not a randomized comparison with the treatment-period group of 506. Comparing the counts as if they arose from equivalent groups would overlook the design and the difference in group size. The registry explicitly cautions that these are not like-for-like control arms.

The record also illustrates the importance of reporting uncertainty and analysis details. It reports counts and selected serious-event percentages, but confidence intervals, missing-data methods, multiplicity procedures, and the detailed statistical plan are not reported in the registry record. Those omissions constrain how precisely results can be interpreted and how secondary outcomes can be assessed.

Finally, the listed efficacy outcomes are not accompanied by numerical results in the registry record. Statistical interpretation must be tied to results that are actually reported, rather than inferred from the study title or outcome names. The main statistical lesson is to distinguish observed event experience from comparative evidence and to state clearly where the registry’s reporting does not support further conclusions.

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 most important limitation for interpreting the safety results is the absence of a randomized control group. The trial is open-label and single-group, so its event counts cannot establish how the observed experience differs from another treatment or from no study treatment. The registry cautions that the extension-period group is not a like-for-like control comparison.

The extension-period figures are based on 11 participants at risk, while the treatment-period figures are based on 506. This difference in group size, together with the extension group’s selection from certain countries, limits direct comparison. The registry does not report details that would support adjustment for differences between the groups.

The primary endpoint counts participants with events but does not provide, in the available record, confidence intervals, event durations, recurrent-event summaries, or a complete account of time at risk. The registry lists selected serious-event terms and percentages, but the denominator and attribution details are not reported in the registry record. One death is recorded, but the record does not establish its cause.

The registry names secondary efficacy outcomes but does not report their numerical results. It also does not report the detailed statistical plan, missing-data methods, multiplicity strategy, or sample-size justification. These gaps limit assessment of the precision and robustness of any broader inference. The reported counts remain useful as descriptive observations, but they cannot resolve these uncertainties or support conclusions beyond the populations and periods recorded.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy — NCT03525574.
• Registry record last updated 2025-09-24; status last verified 2025-09.
• Results first posted 2024-05-08.
• 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

The registry describes a completed Phase 3, open-label, single-group study of VX-445 combination therapy in people with cystic fibrosis who were homozygous or heterozygous for the F508del mutation. Enrollment was 507. The recorded study start date is 2018-10-09, and primary completion was 2023-01-09.

The primary safety outcome counted participants with treatment-emergent adverse events and serious adverse events from Day 1 up to Week 196. The treatment-period safety population included participants who received at least one dose. The registry reports treatment-period serious adverse events among 175 of 506 participants at risk, other adverse events among 501 of 506, and one death. The extension-period group included 11 participants at risk.

Named secondary outcomes cover ppFEV1, sweat chloride, pulmonary exacerbations, and time to first pulmonary exacerbation. Numerical efficacy results and detailed statistical methods are not reported in the registry record. Because there is no randomized control group, the event counts are descriptive rather than comparative.