A Study Evaluating the Long Term Safety and Efficacy of VX-659 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-659 Combination Therapy (NCT03447262), a na phase 3 study. The primary outcome is Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs).

2. Clinical Question

This is a safety-focused question about the experience of participants receiving the triple combination in an open-label study. It is not a randomized estimate of how outcomes differ between treatments. The registry record also lists secondary outcomes concerning percent predicted forced expiratory volume in 1 second (ppFEV1), sweat chloride, and pulmonary exacerbations, separately for participants from each parent study. Their listing identifies outcomes of interest, but does not itself establish their results or how they were analyzed.

3. Trial Design

The registry identifies this as a Phase 3, open-label, single-group study of VX-659 combination therapy in people with cystic fibrosis and the F508del mutation. It lists enrollment as 484 and status as terminated. The study started on 2018-07-13, and primary completion is recorded as 2020-09-09. Those dates describe the registry record; they do not explain why the study ended or whether the planned follow-up was completed.

Participants came from parent studies VX17-659-102 and VX17-659-103. The described treatment period used VX-659 240 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours for up to 96 weeks. The safety outcome timeframe runs from Day 1 through 28 days after the last dose or the completion of study participation date, whichever occurred first, up to Week 100. The regimen and safety timeframe are not the same thing: the former describes treatment, while the latter defines the period over which the primary safety outcome was assessed.

Open-label means that masking was not used, consistent with the registry entry of NONE. The study is not recorded as randomized, and its allocation is NA. Therefore, the registry record does not support interpreting the treatment group as a like-for-like control comparison. The fact that IVA appears in the intervention list does not establish a separate comparison arm; the arm description identifies the VX-659/TEZ/IVA triple combination.

The primary safety population is the open-label safety set, defined as participants who received at least 1 dose in the current study. Its listed size differs from the enrollment figure, but the registry record does not explain the difference. It also does not report the reasons for termination, detailed eligibility criteria, a statistical analysis plan, or the intended handling of participants who did not complete follow-up.

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 12 years or older who participated in parent studies 659-102 or 659-103. Eligible participants from the parent studies were enrolled in the current study 659-105.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Open label safety set (OL-SS) included all participants who received at least 1 dose of study drug in the current study 659-105.

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 Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs), measured over From Day 1 up to 28 Days After Last Dose of Study Drug or to the Completion of Study Participation Date, Whichever Occurs First in the Current Study 659-105 (up to Week 100).

The primary endpoint concerns safety and tolerability, measured as the number of participants with treatment-emergent AEs and SAEs. An AE is an adverse event recorded during the relevant treatment or follow-up period; an SAE is an event categorized as serious under the study’s safety reporting. The endpoint is a count of participants, not a measure of symptom severity, duration, or treatment effect relative to a control group.

Counting participants with events is useful for describing how often events were reported within a treated study population. The distinction between all treatment-emergent AEs and SAEs also helps readers separate the broader set of events from those meeting seriousness criteria. These categories answer a descriptive safety question, but participant counts alone do not establish causation. An event occurring during a study is not, by that fact alone, shown to have been caused by the study drug.

The registry defines the assessment period as beginning on Day 1 and extending to 28 days after the last dose or the completion of study participation date, whichever occurred first, up to Week 100. The defined safety population includes participants who received at least 1 dose. The adverse-event entry lists 481 participants at risk, 99 with serious events, and 446 with other events. These posted counts are descriptive; the registry record does not provide a comparative estimate or a confidence interval for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s primary endpoint is a participant count: the number of people with treatment-emergent AEs and the number with SAEs. This is a descriptive outcome. It differs from an effect estimate comparing two treatment groups, because the study is recorded as single-group and has no randomized comparator. The registry record lists 481 participants at risk for the adverse-event results, with 99 affected by serious events and 446 affected by other events.

What does a participant count convey?

A participant count tells readers how many members of the safety population were recorded as having an event under the study’s reporting definitions and observation period. A participant-based count is not necessarily the same as an event count: a participant may experience more than one event. The registry entry presents affected-participant counts for the safety outcome. It does not report the total number of event episodes for these categories, event duration, or severity beyond the SAE classification.

Counts also depend on who entered the analysis population and how long each person was followed. The primary population is defined as the open-label safety set, including participants who received at least 1 dose. The timeframe starts on Day 1 and ends 28 days after the last dose or at completion of study participation, whichever occurred first, up to Week 100. The registry record does not report participant-level follow-up duration or an exposure-adjusted event rate. Consequently, the counts should not be interpreted as if each participant had necessarily contributed the same time under observation.

Why does the study design matter?

In a randomized comparison, treatment groups can be compared using an effect estimate that reflects differences in their observed outcomes, subject to the design and analysis assumptions. This study is recorded as single-group, with allocation NA and masking NONE. Its adverse-event counts therefore describe the treated group without a randomized control group. They cannot, on their own, show what the event experience would have been under a different treatment or without the study treatment.

Open-label conduct means masking was not used. This can matter for reporting and assessment, especially for outcomes that involve judgment, although the registry record does not describe how event collection or adjudication was carried out. The record does not report a blinded review process, an analysis plan, or methods for controlling confounding. No inference about those procedures should be drawn from the design label alone.

How should uncertainty be understood?

A confidence interval is a statistical tool that expresses the uncertainty around an estimated quantity under a specified method and assumptions. A narrow interval generally indicates greater precision than a wide interval, while neither an interval nor a point estimate alone resolves design limitations or establishes causation. The registry record does not report confidence intervals for the primary safety counts. No interval should be inferred from the counts without a specified analysis and assumptions.

Likewise, a p-value concerns how compatible data are with a statistical model or null hypothesis; it is not the probability that a treatment works, nor does it measure clinical importance. The registry record lists 0 analyses. It does not report a p-value for the primary safety endpoint or a statistical test comparing groups. In the absence of a randomized comparator, a conventional between-group test would not be an analysis of the design described in the record.

What do the listed serious-event percentages mean?

The record lists percentages next to selected serious-event terms: infective pulmonary exacerbation of cystic fibrosis, 8.3%; distal intestinal obstruction syndrome, 1.2%; haemoptysis, 1.0%; influenza, 0.8%; alanine aminotransferase increased, 0.8%; and aspartate aminotransferase increased, 0.8%. The denominator, calculation method, and whether a participant could contribute to more than one term are not reported in the registry record. These percentages should therefore be quoted as listed rather than converted into counts or used to reconstruct a denominator.

In general, over-dispersion occurs when variability in observed counts exceeds what a simpler statistical model assumes. It can make standard errors too small if a model fails to account for extra variability. This is a general consideration for count outcomes, not a claim about the analysis in this study: the registry record does not describe a count model, an over-dispersion assessment, or any such adjustment. The primary endpoint is framed as the number of participants with events, and no inferential model is reported.

How do planning calculations differ from trial results?

Sample-size calculations are planning illustrations, not observed power. The assumptions described for such illustrations are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect expressed as a fraction of the observed effect. Those assumptions do not describe the recorded single-group design, and they do not establish that the study was designed or powered for a randomized comparison. No sample-size justification or calculation outputs are reported in the registry record. The record also does not report an observed treatment effect from which to make an independent power claim.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 17 outcome measures and 0 analyses. It names secondary outcomes for ppFEV1, sweat chloride, and pulmonary exacerbations, with outcomes identified separately for participants from parent studies 659-102 and 659-103. The presence of several outcomes raises a general multiplicity consideration: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan addresses that issue.

The registry record does not report which outcomes were formally tested, whether any multiplicity adjustment was planned, or how outcomes were prioritized beyond identifying the primary safety endpoint. It also does not report a statistical analysis plan or the results of inferential tests. Therefore, no claim about multiplicity control or the interpretation of secondary-outcome tests can be made from the record.

Missing-data methods are not reported in the registry record. The primary safety population includes participants who received at least 1 dose, but the record does not describe how incomplete safety follow-up, withdrawal, or missing outcome information was handled. It does not report imputation, censoring rules beyond the stated safety timeframe, or sensitivity analyses. These omissions limit assessment of whether missing observations could affect the descriptive results.

The primary population is explicitly defined as the open-label safety set. The registry does not report an intention-to-treat analysis population or give a separate population definition for the secondary outcomes. It also does not explain the difference between enrollment of 484 and the 481 participants listed at risk for adverse events. These figures should be read as separate registry entries rather than reconciled by assumption.

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 (8.3%), distal intestinal obstruction syndrome (1.2%), haemoptysis (1.0%), influenza (0.8%), alanine aminotransferase increased (0.8%).

The adverse-event entry lists 481 participants at risk, 99 affected by serious adverse events, and 446 affected by other adverse events. It also lists 2 deaths. These are registry-reported counts. The record does not state whether participants could be included in both affected categories, so the counts should not be added together or treated as mutually exclusive.

The selected serious-event terms are accompanied by percentages: infective pulmonary exacerbation of cystic fibrosis, 8.3%; distal intestinal obstruction syndrome, 1.2%; haemoptysis, 1.0%; influenza, 0.8%; alanine aminotransferase increased, 0.8%; and aspartate aminotransferase increased, 0.8%. The denominator and calculation method for these percentages are not reported in the registry record. They should not be used to derive counts.

SAE classification describes seriousness, not necessarily causal relationship to treatment. The registry record does not provide a treatment-relatedness assessment for these figures or causes for the deaths. Because the study has no randomized control group, these data describe events observed in the treated group but do not establish how event rates compare with another treatment or what caused an event.

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

The posted results describe adverse events recorded during an open-label study of VX-659 with TEZ and IVA in participants with cystic fibrosis who were homozygous or heterozygous for the F508del mutation. The record identifies 99 participants with serious adverse events and 446 with other adverse events among 481 listed at risk, as well as 2 deaths. These figures provide a descriptive account of reported safety events in the defined population and timeframe.

They do not show that VX-659 combination therapy caused the events, nor do they show how the treatment compares with another regimen. There is no randomized comparator in the design recorded by the registry. Event counts can reflect many influences, and the record does not provide a causal analysis or comparative estimate. The listed serious-event percentages also lack a reported denominator and calculation method, so they should be interpreted only as reported values.

The endpoint is a count of participants with AEs and SAEs, not a measure of the treatment’s effect on lung function, sweat chloride, or pulmonary exacerbations. Those outcomes are listed as secondary measures for parent-study groups, but their names alone do not establish results. The registry record does not report statistical analyses, confidence intervals, or a detailed analysis plan.

The study status is terminated. That status, by itself, does not explain why the study ended, whether it ended early relative to a plan, or whether the termination was related to safety. The reason is not reported in the registry record. The record also does not report whether every participant completed the intended follow-up.

Accordingly, the safety figures are best understood as descriptive observations from the registry record. They neither establish treatment benefit nor determine treatment-related harm. Any broader interpretation would require clinical context and analytical details not reported in the record.

13. Why This Trial Matters Statistically

This study illustrates why a numerical safety result must be read alongside the design that generated it. Counts of participants with adverse events can be useful for describing a treated population, but without a randomized comparison they do not estimate how outcomes differ between treatments. The registry identifies the study as open-label and single-group, so the central statistical contribution of the posted safety figures is descriptive rather than comparative.

It also demonstrates the importance of defining the analysis population and observation window. The primary safety set includes participants who received at least 1 dose, and the timeframe extends from Day 1 through 28 days after the last dose or completion of study participation, whichever occurred first, up to Week 100. Event counts have meaning only in relation to such definitions. Variation in follow-up and the handling of missing observations can affect interpretation, but those details are not reported in the registry record.

Another statistical lesson is that event counts, event percentages, and causal conclusions are not interchangeable. The registry lists counts for serious and other adverse events, selected serious-event percentages, and deaths. It does not report the denominator or calculation method for the term-specific percentages, nor does it establish treatment causation. Reporting these quantities clearly while avoiding unsupported comparisons is essential to accurate interpretation.

Finally, the record lists multiple outcome measures but no analyses. That distinction matters: registering an outcome does not establish that it was analyzed, and a list of outcomes does not reveal how multiplicity or missing data were handled. The study is therefore a useful case for separating what the registry reports from what a statistical reader might want to know but cannot establish from the record.

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 is the single-group, open-label design. There is no randomized control comparison, so the adverse-event counts cannot estimate relative risk or isolate treatment effects from other influences. The registry lists allocation as NA and masking as NONE; it does not report procedures that would permit a causal comparison.

The record gives enrollment as 484, while the adverse-event entry lists 481 at risk. The reason for this difference is not reported in the registry record. The safety population is defined by receipt of at least 1 dose, but the record does not provide participant-level follow-up, time exposed, or the number with complete safety follow-up. Counts therefore cannot be adjusted for differences in observation time using the available information.

The registry record does not report the reasons the study was terminated, whether termination changed planned follow-up, or whether any safety findings contributed to the decision. It does not provide detailed eligibility criteria, the analysis plan, methods for missing data, confidence intervals, or inferential analyses. For selected serious-event terms, it lists percentages but not the denominator or calculation method.

The adverse-event results are descriptive and do not establish that events were caused by treatment. The record does not provide causes for the listed deaths or a detailed treatment-relatedness assessment. These limitations restrict interpretation to the figures and definitions actually recorded; they do not justify assumptions about unreported trial procedures or results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study Evaluating the Long Term Safety and Efficacy of VX-659 Combination Therapy — NCT03447262.
• 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

NCT03447262 is a Phase 3, open-label, single-group study of VX-659 in combination with TEZ and IVA for participants with cystic fibrosis who were homozygous or heterozygous for the F508del mutation. The registry lists enrollment as 484, status as terminated, a start date of 2018-07-13, and primary completion on 2020-09-09. Participants came from parent studies VX17-659-102 or VX17-659-103, and the described triple-combination treatment period was up to 96 weeks.

The primary endpoint concerns participant counts for treatment-emergent AEs and SAEs. The safety population includes participants who received at least 1 dose; the adverse-event entry lists 481 at risk, 99 with serious events, 446 with other events, and 2 deaths. Selected serious-event terms are reported with percentages. The registry record lists 17 outcome measures and 0 analyses. It does not report a randomized comparison, statistical analysis plan, missing-data methods, or the reason for termination.