A Study to Evaluate the Safety and Efficacy of Long Term Treatment With VX-661 in Combination With Ivacaftor in Participants With Cystic Fibrosis Who Have an F508del-CFTR Mutation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety and Efficacy of Long Term Treatment With VX-661 in Combination With Ivacaftor in Participants With Cystic Fibrosis Who Have an F508del-CFTR Mutation (NCT02565914), a na phase 3 study. The primary outcome is Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs).

2. Clinical Question

The central question is therefore descriptive: what adverse events were recorded among participants receiving the study treatment during follow-up? Because there is no concurrent comparator, the event counts cannot by themselves establish whether the observed events were more or less frequent than they would have been without the study treatment. Nor can the rollover design isolate a treatment effect from changes over time, participants’ prior treatment, or the clinical course of cystic fibrosis.

3. Trial Design

This was a Phase 3, multicenter, open-label rollover study with three parts. It evaluated long-term treatment with VX-661 in combination with ivacaftor in people with cystic fibrosis who were homozygous or heterozygous for the F508del-CFTR mutation. The official title specifies participants aged 12 years and older. The registry classifies the study as single-group, with no allocation to randomized treatment arms and no masking.

Participants came from earlier studies identified in the registry as VX13-661-103, VX14-661-106, VX14-661-107, VX14-661-108, VX14-661-109, VX14-661-111, VX15-661-112, and VX16-661-114. The rollover arrangement means this study followed participants from those parent studies; it was not a randomized comparison of the combination treatment against a concurrent control group. The registry reports enrollment of 1131.

For Part A, the treatment description states that participants received TEZ 100 milligram/IVA 150 mg in a fixed-dose tablet in the morning and IVA 150 mg in the evening for 96 weeks. The treatment descriptions for the other parts are not fully reported in the registry record. The registry lists TEZ/IVA and IVA as interventions, but that listing does not create a controlled comparison in the current study.

The study started in 2015-08, reached primary completion in 2019-05, and is marked completed. Its primary outcome was safety and tolerability, assessed by the number of participants with treatment-emergent adverse events and serious adverse events from Day 1 up to Week 100. The registry lists changes in percent predicted forced expiratory volume in 1 second as secondary outcomes for efficacy sets linked to parent studies. Numerical results for those secondary outcomes are not reported in the registry record.

4. Participant Flow and Accounting

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

Before assignment: A total 1131 participants enrolled in the study (1044 in Part A, 464 in Part B and 204 in Part C).

Part A (Up to 96 Weeks)

Reasons for not completing this period:

Part B (Up to 96 Weeks)

Reasons for not completing this period:

Part C (Up to 192 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Set was defined as all participants who received at least 1 dose of study drug.

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: Baseline data is based on the parent study baseline, which is defined as the most recent non-missing measurements collected before the first dose of the study drug in the treatment period of parent studies. Baseline data is presented for all participants who signed informed consent and enrolled, or dosed, in Part A, Part B, or Part C, respectively in this study.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs), measured over Day 1 up to Week 100.

The primary endpoint counts participants with treatment-emergent adverse events and serious adverse events during the stated observation period, from Day 1 up to Week 100. The registry defines the safety set as participants who received at least one dose of study drug. The result is therefore a participant count, rather than a count of every event episode or a measure of event severity averaged across the group.

Safety and tolerability outcomes are used to describe what was observed during treatment and follow-up. Reporting serious adverse events separately from other treatment-emergent adverse events helps distinguish events meeting the serious-event classification from the broader set of recorded adverse events. These counts are descriptive: without a concurrent control group, they do not show how many events would have occurred in the absence of treatment or establish that treatment caused an event.

The registry reports the observation window and safety-set definition, but does not report a detailed operational definition of treatment-emergent, rules for attributing events to treatment, or an analysis method for the primary endpoint. Those details are not reported in the registry record. The outcome title also does not specify whether each participant is counted once within each event category or how repeated events are handled beyond describing the measure as a number of participants.

The secondary outcomes concern absolute and relative change in percent predicted forced expiratory volume in 1 second for several parent-study efficacy sets. These are distinct from the primary safety endpoint. Their numerical estimates and uncertainty are not reported in the registry record, so they cannot be interpreted as evidence of the size or precision of an efficacy change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count describe?

The primary outcome is expressed as the number of participants who experienced events, with a denominator for each part. A participant count answers whether an event was recorded for participants during the specified period; it is not the same as counting every event episode. One participant may have more than one event, and event counts, participant counts, and rates based on time at risk answer different questions. The registry identifies the primary outcome as a count of participants, but further rules for handling repeated events are not reported in the registry record.

What does the safety population mean?

The safety set includes everyone who received at least one dose of study drug. This is a treatment-exposed population, rather than necessarily every person enrolled. The registry gives separate denominators for the three parts, but does not describe all participant flow or explain how participants were assigned to each part. These denominators should be interpreted within their listed parts, not combined into a new overall total.

Why does the design matter for interpretation?

General: Randomization and a concurrent control group help distinguish treatment effects from other explanations for differences in outcomes. An open-label, single-group study does not provide that controlled contrast. Its observed event counts can describe what occurred among participants receiving treatment, but they cannot by themselves estimate what would have happened to comparable participants under another treatment or without the study treatment. Open-label follow-up can also affect event reporting and assessment; the record does not report additional safeguards or assessment procedures.

General: A rollover design follows people who took part in parent studies. That context may make long-term observation possible, but it also means the enrolled population has prior study experience and may not represent all people with the condition. The registry names the parent studies but does not report the selection process, reasons for entering or not entering the rollover study, or how prior treatment histories were accounted for in analysis.

How should event proportions and uncertainty be considered?

General: A participant count paired with a denominator can be expressed as a proportion, while a confidence interval can convey the statistical uncertainty around an estimate. A confidence interval describes a range of values reasonably compatible with the data under the analysis assumptions; it does not remove design limitations or demonstrate causation. The registry record does not report confidence intervals for the primary safety outcome, so the precision of the posted counts cannot be evaluated from an interval estimate.

General: When observations are correlated, such as repeated events within a participant, methods that treat every event as independent may understate uncertainty. Approaches can account for clustering or repeated measures, depending on the outcome and analysis question. The registry record does not report whether repeated-event methods were used, and the primary endpoint is described as a count of participants rather than a count of event episodes.

What analysis plan is reported?

The registry gives the primary endpoint, its observation window, and the safety-set definition. It does not report the statistical model, inferential testing procedure, confidence-interval method, missing-data procedure, or a prespecified analysis plan for the primary endpoint. It also does not report whether interim analyses were planned or conducted. These omissions mean that the posted counts should be read as descriptive results, rather than as a complete account of a prespecified inferential analysis.

The record lists 37 outcome measures and several secondary efficacy outcomes relating to absolute and relative changes in percent predicted forced expiratory volume in 1 second. It names efficacy sets associated with parent studies, but definitions of those sets and numerical estimates are not reported in the registry record. The record therefore does not allow assessment of how those analyses handled baseline values, repeated measurements, missing visits, or multiplicity.

How do planning calculations differ from trial results?

General: A sample-size calculation is a planning illustration about the amount of information that might be needed to detect a stated effect under specified assumptions. It is not an observed result and is not observed power. The registry describes planning assumptions of a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect defined as a stated fraction of an observed effect. Those assumptions do not convert this single-group rollover study into a randomized two-arm trial. The original trial’s sample-size justification is not reported in the registry record, and no planning estimate should be interpreted as evidence that the study had a particular probability of finding an effect.

General: Statistical significance and clinical importance are different considerations. A small estimated effect may be statistically precise, while a larger estimate may remain uncertain; neither conclusion can be drawn without the estimate, its uncertainty, and an appropriate analysis. For this record, the primary safety counts are available, but the registry does not report a comparative efficacy estimate or its uncertainty. The appropriate interpretation is therefore bounded by the descriptive information that is recorded.

10. Multiplicity, Missing Data and Analysis Populations

The record lists a broad set of outcomes. The primary outcome concerns treatment-emergent adverse events and serious adverse events, while the secondary outcomes include absolute and relative changes in percent predicted forced expiratory volume in 1 second for efficacy sets linked to parent studies. When multiple outcomes or analyses are considered, the chance of at least one apparently notable result can increase. Statistical approaches can address that issue, but the multiplicity strategy for this study is not reported in the registry record. No correction or hierarchy for interpreting the listed secondary outcomes is specified.

The record defines the safety set as all participants who received at least one dose of study drug. It names several efficacy sets but does not give their full definitions or participant flow. It is therefore not possible to determine from the registry record how many participants contributed data to each efficacy outcome or how the analysis populations related to enrollment.

The registry does not report how missing outcome measurements, missed visits, withdrawals, or incomplete follow-up were handled. It also does not describe whether missingness was assessed or whether sensitivity analyses were performed. These details matter because the available observations may differ from all outcomes that would have been collected under complete follow-up.

The primary observation window is stated as Day 1 up to Week 100, but detailed follow-up and censoring rules are not reported in the registry record. Without those rules and an analysis plan, the counts can be described as posted, but their completeness and the handling of incomplete observation cannot be independently assessed.

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 (23.3%), haemoptysis (2.9%), drug hypersensitivity (1.5%), distal intestinal obstruction syndrome (1.2%), pneumonia (0.9%).

The serious adverse event counts are reported separately for each part: 351 of 1042 participants in Part A, 136 of 463 in Part B, and 44 of 204 in Part C. The registry lists other adverse events for the same part-specific denominators: 938 of 1042 in Part A, 391 of 463 in Part B, and 149 of 204 in Part C. The record also reports 1 death in Part A and 0 in each of Parts B and C.

These counts describe participants with recorded events; they are not event rates adjusted for duration of exposure, and they do not indicate the number of separate event episodes. The registry does not report the calculation method for the listed serious-event term percentages or their denominator. The listed terms include infective pulmonary exacerbation of cystic fibrosis (23.3%), haemoptysis (2.9%), drug hypersensitivity (1.5%), distal intestinal obstruction syndrome (1.2%), pneumonia (0.9%), and constipation (0.8%).

Because the study has no concurrent control group, these figures do not estimate the difference in risk attributable to treatment. The registry record also does not provide event-level timing, duration, or outcome details needed to interpret individual cases.

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

The posted results show that adverse events, including serious adverse events, were recorded among participants in all three parts of this long-term rollover study. The counts provide a descriptive account of participants with events during the stated safety observation period. The listed serious adverse event terms give additional context about events recorded in the registry.

They do not establish that the study treatment caused any particular event. Cystic fibrosis is the underlying condition, participants entered from parent studies, and no concurrent control group was included in the registry’s single-group design. Without a suitable comparison, the observed counts cannot show whether an event was more common because of treatment, less common because of treatment, or related to other factors.

The counts also do not establish how the results would apply to people who did not participate in the parent studies or who were not eligible for this rollover study. The registry record does not report detailed participant flow, the completeness of follow-up, or a method for addressing missing outcome data. These limitations restrict what can be inferred about long-term safety beyond the recorded participants and observation period.

The registry lists efficacy outcomes based on changes in percent predicted forced expiratory volume in 1 second, but their numerical results are not reported in the registry record. The safety counts therefore should not be read as a measure of efficacy, and they do not establish the size or precision of any change in lung function. The study’s posted primary results support a description of observed event counts, not a controlled estimate of treatment benefit or harm.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between long-term safety description and controlled treatment-effect estimation. A rollover study can observe participants after parent studies, and its safety population and observation window make clear what group and period the reported counts concern. That information is useful for understanding what was recorded during follow-up.

At the same time, study design determines the scope of the conclusions. The registry identifies the study as open-label and single-group, with no randomized concurrent control. Consequently, the participant counts are not comparative effects. They cannot separate treatment-related events from events due to the underlying condition, prior treatment, or other influences. More follow-up does not by itself replace a control group or resolve confounding.

The distinction between participant counts and event episodes also matters. A count of participants with an event answers a different question from a count of all events or an exposure-adjusted rate. Clear reporting of definitions, follow-up, and analysis methods is needed to interpret those measures precisely. Several such details, including methods for missing data and multiplicity, are not reported in the registry record.

Finally, the record lists lung-function outcomes but does not report their numerical results. This makes the separation between outcome listing and result reporting important: a listed outcome alone is not evidence of an observed change. The statistical contribution available from this record is thus primarily a description of safety counts, with substantial limits on comparative and efficacy interpretation.

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.

This study has no randomized comparator and was open-label. Its three parts are not like-for-like treatment arms, and the registry does not establish that their participants are independent. The counts from separate parts should therefore be interpreted separately rather than combined into an overall estimate or treated as comparative effects.

Participants rolled over from specified parent studies, so the study population was selected from people who had participated in those trials. The registry record does not report the selection process, participant flow, or how prior treatment and exposure were addressed in the analysis. This limits interpretation of how representative the observed results may be beyond the rollover population.

The registry reports the primary safety endpoint, the observation window, and the safety-set definition, but does not report detailed event definitions, attribution rules, statistical methods, confidence intervals, or a full analysis plan. It also does not report handling of missing data, withdrawals, or incomplete follow-up. The calculation method and denominator for the listed serious-event term percentages are not reported.

Although several secondary lung-function outcomes are listed, their numerical results are not reported in the registry record. Multiplicity procedures, efficacy-set definitions, and numerical estimates for those outcomes are also not reported. The study’s original sample-size justification, interim analyses, and detailed treatment descriptions for all parts are not reported in the registry record. These gaps limit assessment of precision, completeness, and the intended inferential framework.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety and Efficacy of Long Term Treatment With VX-661 in Combination With Ivacaftor in Participants With Cystic Fibrosis Who Have an F508del-CFTR Mutation — NCT02565914.
• Registry record last updated 2023-09-28; status last verified 2023-09.
• Results first posted 2020-06-16.
• 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

NCT02565914 is a completed, multicenter, open-label, Phase 3 rollover study of long-term VX-661 in combination with ivacaftor in participants with cystic fibrosis and an F508del-CFTR mutation. The official title specifies participants aged 12 years and older. The study is classified as single-group, and the registry reports enrollment of 1131.

The primary outcome is the number of participants with treatment-emergent adverse events and serious adverse events from Day 1 up to Week 100. The safety set includes participants who received at least one dose of study drug. The posted results give part-specific adverse event counts and deaths. The record also lists secondary lung-function outcomes, but their numerical results are not reported in the registry record.

Because there is no concurrent control group, the safety counts are descriptive and do not estimate comparative treatment effects. Detailed statistical methods, missing-data handling, and multiplicity procedures are not reported in the registry record.