Rollover Study to Evaluate the Safety and Efficacy of Long-term Treatment With Lumacaftor in Combination With Ivacaftor: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Rollover Study to Evaluate the Safety and Efficacy of Long-term Treatment With Lumacaftor in Combination With Ivacaftor (NCT02544451), a non-randomized phase 3 study. The primary outcome is Treatment Period 1 (Treatment Cohorts): Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs).

2. Clinical Question

3. Trial Design

This completed Phase 3 study was designed to evaluate the safety and efficacy of long-term lumacaftor in combination with ivacaftor in cystic fibrosis. Participants were aged 6 years and older and homozygous for the F508del-CFTR mutation. They had previously participated in Study 109 or Study 011B. The registry describes the study as multicenter and reports enrollment of 246 participants.

The allocation is recorded as non-randomized, masking as none, and the model as parallel. These design features matter when interpreting group results: the groups were not formed by random assignment, and participants and study personnel were not masked to treatment allocation. The listed treatment histories include LUM/IVA to LUM/IVA and placebo to LUM/IVA in Treatment Period 1, an observational cohort, and LUM/IVA in Treatment Period 2. The registry does not provide fuller descriptions of these arms or the reasons participants entered each group.

The study began in 2015-08, reached primary completion in 2018-08, and is recorded as completed. The sponsor was Vertex Pharmaceuticals Incorporated. The primary outcome was a safety measure, with the timeframe stated as Day 1 up to Week 100. Its safety population included all participants who received at least 1 dose of study drug in Treatment Period 1. The registry record does not report a sample-size justification, detailed allocation procedures, or additional protocol-level explanations of the treatment periods.

The study also listed outcomes covering lung clearance index, sweat chloride, body mass index, respiratory quality-of-life score, serious adverse events in the observational cohort, and absolute and relative changes in percent predicted forced expiratory volume in 1 second. Those listed outcomes indicate a broader assessment than safety alone, but numerical results for them are not reported in the registry record addressed.

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: Participants from Parent Studies 109 (NCT02514473) and 011B (NCT01897233) were enrolled in this study. A total of 240 participants were enrolled in Treatment Period 1 Treatment Cohorts, out of which 1 participant was enrolled but never dosed. Participants enrolled in the Observational and Treatment Period 2 Cohorts were followed for safety endpoint only, no efficacy data were collected.

Treatment Period 1 (96 Weeks)

Reasons for not completing this period:

Treatment Period 2 (168 Weeks)

Reasons for not completing this period:

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

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: Treatment Cohort: All participants dosed in the parent studies and dosed in the current study. Observational Cohort: All participants enrolled in the observational cohort of the current study.

6. Primary Endpoint

The registry lists the primary outcome as Treatment Period 1 (Treatment Cohorts): 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 outcome counts participants with treatment-emergent adverse events and serious adverse events during Treatment Period 1, over the stated timeframe of Day 1 up to Week 100. It is a participant-count endpoint, rather than a measure of the total number of adverse-event episodes. The distinction is important: a participant with repeated events may still contribute as a participant with an event, while the count does not describe event recurrence or duration.

Safety and tolerability outcomes are used to describe unwanted events observed during treatment exposure. Serious adverse events are a subset of particular clinical importance, while the broader adverse-event count captures events that do not meet the serious category. The registry reports numbers of participants at risk and numbers affected for the listed groups. These descriptive counts can show how many participants were recorded as having events, but by themselves do not establish that treatment caused an event or explain how risk compares across groups.

The defined safety population includes participants who received at least 1 dose of study drug in Treatment Period 1. The registry does not state further details about event collection, coding rules, adjudication, or handling of participants with incomplete follow-up. It also does not report a primary-outcome comparison estimate, confidence interval, or hypothesis test. Thus the endpoint is useful for describing recorded safety experience, but the posted data do not quantify comparative uncertainty or a causal treatment effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is expressed as the number of participants affected. For a binary participant-level outcome, each participant is classified according to whether the event occurred during the specified observation period. A count is easy to interpret as a description of the study population, but it does not show how many episodes occurred, how long events lasted, or when they arose. The registry provides counts at risk and affected for serious and other adverse events in the listed groups.

What do the counts describe?

The “at risk” figures identify the group sizes used for the registry’s adverse-event summaries. The affected figures indicate how many participants were recorded with the event category. These figures should be read within their named treatment period and cohort. They are not interchangeable denominators: Treatment Period 1 groups, an observational cohort, and a Treatment Period 2 group represent distinct entries. In particular, the observational cohort’s other-adverse-event denominator is recorded as 0, so its 0 affected entry cannot be interpreted as evidence that no participant in that cohort experienced an event.

General statistical explanation: a proportion is often used to put a count in context by relating affected participants to the group at risk. Such a summary remains descriptive, and precision depends on the amount of information in the group. No new proportion or uncertainty interval is calculated. The registry record does not report confidence intervals or standard errors for the posted counts. A confidence interval, in general, describes a range of values compatible with the data under a specified statistical model; it is not a guarantee that the true value lies in that range.

Why is this not a randomized comparison?

The study is recorded as non-randomized, with no masking. Random assignment can help balance measured and unmeasured characteristics between groups on average; the registry does not describe that process. In a rollover study, the listed groups also have different treatment histories, and one group is observational. Their counts may reflect differences in participant characteristics, prior treatment, follow-up, or group selection as well as treatment exposure. Without a suitable comparative design and a stated analysis, a numerical difference between counts cannot be attributed to treatment.

The primary outcome timeframe extends from Day 1 up to Week 100. Follow-up duration and time exposed can affect opportunities to record events. The registry record does not report individual follow-up duration, a time-at-risk analysis, or a method for accounting for different exposure times. Counts of participants affected therefore do not describe event rates per unit of exposure. They also do not convey event severity beyond the distinction between serious and other adverse events.

What analyses are reported?

The record lists 22 outcome measures and 0 analyses. The displayed safety information is descriptive. No p-values, adjusted estimates, confidence intervals, or model specifications are reported for the primary outcome. The registry record does not report a prespecified statistical analysis plan, covariate adjustment, interim analyses, or a sample-size justification. These omissions mean that the inferential framework and any planned handling of multiple outcomes cannot be established from the record.

The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. For time-to-event outcomes, the illustration is defined in terms of total events; other illustrations are defined as participants per arm. Such planning values, where displayed, are not observed power and do not substitute for the trial’s own design justification. The registry does not report that justification. With no randomized comparison and no reported inferential effect estimate for the primary safety outcome, those assumptions should not be mistaken for a formal analysis of the trial results.

General statistical explanation: over-dispersion occurs when observed variability is greater than a model assumes. It matters when a model’s uncertainty estimates rely on an overly restrictive variance assumption. The posted primary outcome is a participant count, and no model-based analysis is reported, so the record does not establish whether over-dispersion was assessed or relevant to a particular fitted model.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 22 outcome measures, including safety outcomes and changes in lung clearance index, sweat chloride, body mass index, respiratory-domain score, and percent predicted forced expiratory volume in 1 second. When many outcomes are evaluated, the chance of finding an apparently notable result by chance can increase if each is tested separately. A multiplicity strategy may address this issue, for example by prioritizing an outcome or adjusting inference across tests. The registry record does not report such a strategy, and it reports 0 analyses. Without analysis results and a stated plan, it is not possible to determine which outcomes were formally tested or how multiplicity was handled.

Missing-data methods are not reported in the registry record. The safety population is defined as participants who received at least 1 dose of study drug in Treatment Period 1, but the record does not explain how incomplete observation, withdrawal, or missing outcome measurements were handled. The counts at risk give group denominators for the listed safety summaries; they do not, on their own, describe missingness or show whether all participants were followed for the full stated timeframe.

The record also does not report an analysis population for the listed efficacy outcomes, the handling of protocol deviations, or whether any sensitivity analyses were performed. These details matter because analytic choices can affect estimates and their uncertainty. In their absence, interpretation should remain with the descriptive safety counts and the stated safety-set definition, rather than assuming a particular missing-data or multiplicity procedure.

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 (23.8%), constipation (2.8%), pulmonary function test decreased (2.1%), alanine aminotransferase increased (2.1%), aspartate aminotransferase increased (2.1%).

For Treatment Period 1, the registry lists 43 of 143 participants affected by serious adverse events in the LUM/IVA-to-LUM/IVA group, and 29 of 96 in the placebo-to-LUM/IVA group. The corresponding other-adverse-event entries are 141 of 143 and 93 of 96. These are counts within non-randomized groups, not a controlled estimate of relative safety. The observational cohort lists 1 of 6 for serious adverse events; its other-event denominator is 0. Treatment Period 2 lists 0 of 10 for serious adverse events and 9 of 10 for other adverse events. The record lists 0 deaths in each group.

Serious adverse events and other adverse events are separate categories in the record. A participant may have more than one event, but the primary endpoint counts participants, not episodes. The listed serious-event terms and percentages describe the record’s event listings; the denominator for those percentages is not reported in the registry record. The group counts do not establish causation, account for exposure time, or provide uncertainty intervals. Differences should be interpreted cautiously because the groups were not randomized and do not constitute a like-for-like control comparison.

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

The registry record supports a description of safety observations in the named study groups and periods. It reports counts of participants affected by serious and other adverse events, the corresponding group sizes, and 0 deaths in each listed group. It also identifies several serious-event terms and attaches percentages to them. These details characterize events recorded during the study, but they do not amount to a comparative estimate of treatment effect.

The study was non-randomized and unmasked. The groups have different treatment histories, and the observational cohort and Treatment Period 2 group are distinct from the Treatment Period 1 treatment groups. Differences in participant selection, baseline characteristics, prior treatment, or time under observation may contribute to differences in recorded counts. The registry does not provide an adjusted analysis or information sufficient to resolve those possibilities. The counts cannot establish that LUM/IVA caused or prevented a particular event.

The record’s primary outcome is safety and tolerability, not a reported numerical efficacy result. Although secondary outcomes include changes in lung function, sweat chloride, body mass index, and respiratory-domain score, their numerical results are not reported in the registry record addressed. Thus the record does not establish the size or precision of changes in those measures. The absence of reported numerical results should not be treated as evidence that no change occurred.

More broadly, counts alone do not show event timing, recurrence, severity beyond the recorded categories, or rates adjusted for time exposed. The registry does not report confidence intervals or hypothesis tests for the safety counts. The appropriate interpretation is limited to the recorded descriptive data and the stated study design. It does not support a causal conclusion or a claim about comparative efficacy.

13. Why This Trial Matters Statistically

Rollover studies address a question that differs from a conventional randomized efficacy trial: they can document longer-term observations among participants who entered from earlier studies. In this study, the population had cystic fibrosis and was homozygous for the F508del-CFTR mutation, and the study evaluated long-term LUM/IVA treatment. The extended timeframe, stated as Day 1 up to Week 100 for the primary outcome, makes the definition of the safety population and the interpretation of exposure especially relevant.

Statistically, the study illustrates why a large enrollment figure does not by itself guarantee a precise treatment comparison. The registry reports enrollment of 246, but the listed groups differ in treatment history and include an observational cohort. Allocation was non-randomized, and masking was absent. These features limit the extent to which simple group counts can be interpreted as a causal comparison, regardless of the overall enrollment.

The record also distinguishes participant counts from event counts. The primary outcome asks how many participants experienced treatment-emergent adverse events and serious adverse events; it does not summarize the number of episodes per person. This matters when reading safety summaries because recurrence and exposure-adjusted rates answer different questions from participant-level counts.

Finally, the record lists a broad set of secondary outcomes but reports 0 analyses. That separation between outcome registration and reported statistical analysis is important for readers: a listed measure is not itself a result. Clear reporting of estimates, uncertainty, analysis populations, missing-data handling, and multiplicity procedures would be needed to support broader inferential conclusions. The available record therefore highlights both the value and the limits of descriptive long-term safety data.

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 main trial-specific limitation is the non-randomized design. The listed groups have different treatment histories, and the record itself notes that the arms are not a like-for-like control comparison. With no masking, event reporting and assessment may also be influenced by knowledge of treatment, although the registry does not describe how events were assessed. The data therefore do not isolate treatment effects from group differences or other influences.

The safety summaries are counts of affected participants over a timeframe extending to Week 100. The registry does not report individual follow-up duration, time at risk, or exposure-adjusted event rates. A participant count does not describe repeated events, event timing, or duration. The denominator of the listed serious-event percentages is not reported in the registry record. In addition, the observational cohort’s other-event denominator is recorded as 0, limiting interpretation of that entry.

The registry record does not report confidence intervals, p-values, adjusted estimates, a statistical analysis plan, missing-data methods, or a multiplicity strategy. It lists 22 outcome measures but 0 analyses, and numerical efficacy results for the listed secondary outcomes are not reported. Arm descriptions are blank, so the rationale and detailed composition of the listed groups are not explained in the record. These gaps constrain assessment of precision, comparability, and analysis choices. The reported data are best read as descriptive safety information rather than evidence of a causal or comparative effect.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Rollover Study to Evaluate the Safety and Efficacy of Long-term Treatment With Lumacaftor in Combination With Ivacaftor — NCT02544451.
• Registry record last updated 2021-05-24; status last verified 2021-02.
• Results first posted 2019-10-29.
• 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 3, multicenter, non-randomized, unmasked study evaluated long-term lumacaftor in combination with ivacaftor in people aged 6 years and older with cystic fibrosis who were homozygous for the F508del-CFTR mutation and had participated in Study 109 or Study 011B. Enrollment was 246. The study began in 2015-08, primary completion was 2018-08, and the sponsor was Vertex Pharmaceuticals Incorporated.

The primary outcome assessed treatment-emergent adverse events and serious adverse events in Treatment Period 1, from Day 1 up to Week 100. The registry reports participant counts for serious and other adverse events in the listed treatment groups, an observational cohort, and Treatment Period 2; it lists 0 deaths in each group. The record lists secondary outcomes spanning lung function and other clinical measures, but reports 0 analyses. Numerical efficacy results, inferential estimates, missing-data procedures, multiplicity methods, and a sample-size justification are not reported in the registry record.