A Study Evaluating the Long-Term Safety of Elexacaftor Combination Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Evaluating the Long-Term Safety of Elexacaftor Combination Therapy (NCT04362761), 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 (TEAEs) and Serious Adverse Events (SAEs).

2. Clinical Question

The study is an open-label extension in participants with cystic fibrosis who are homozygous for F508del. Its stated focus is the long-term safety and tolerability of the triple combination. Because treatment was open label and the study is listed as single-group, the posted safety counts describe events among treated participants; they do not estimate how those counts would compare with an untreated or randomized control group.

The record separates the safety summaries into Part A and Part B. For the primary endpoint, the relevant population is the safety set, defined as participants who received at least 1 dose of study drug. The registry’s primary outcome description focuses on Part A and specifies observation from Day 1 up to Week 52. The Part B counts are also posted, but the record does not provide a comparative analysis linking the two parts.

Thus the central question is descriptive: what adverse-event counts are recorded during the study? The information can characterize the event experience documented in this record, but it cannot by itself establish whether treatment caused an event or how its safety compares with another treatment.

3. Trial Design

The registry identifies this as a Phase 3b, open-label extension study evaluating elexacaftor/tezacaftor/ivacaftor in cystic fibrosis. The listed model is single-group, masking is none, and allocation is not applicable. These design features mean the posted results are not a randomized comparison between treatment groups. The record lists Vertex Pharmaceuticals Incorporated as the sponsor and gives the study status as completed.

The brief summary describes the intended population as participants with cystic fibrosis who are homozygous for F508del. The primary outcome population is the safety set: participants who received at least 1 dose of study drug. The record gives an enrollment of 172. The Part A safety counts list 172 participants at risk for serious adverse events and 172 at risk for other adverse events. Part B counts list 50 at risk in each of those categories. The relationship between the Part A and Part B participants is not described in the posted information, so those groups should not be assumed to be independent or directly comparable.

The intervention description gives an ELX/TEZ/IVA regimen for Part A, with treatment for 48 weeks, and a regimen for Part B described as continuing up to 86 weeks. The primary outcome timeframe is different in wording: it is from Day 1 up to Week 52. The record also lists ivacaftor as an intervention, but does not explain its role in a separate comparison within the posted safety results.

The registry lists a study start of 2020-05-04 and a primary completion date of 2022-12-21. The record does not report the protocol rationale for the study structure, a sample-size justification, or details of any planned interim analyses. Those design details cannot be inferred from the completion status or from the posted 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: The study was conducted in 2 parts, Part A and Part B. Participants from Part A also participated in Part B. The Participant flow was planned to be presented for the overall treatment arm.

Part A (48 Weeks)

Reasons for not completing this period:

Part B (86 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.

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 participants who received at least 1 dose of study drug 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 (TEAEs) and Serious Adverse Events (SAEs), measured over From Day 1 up to Week 52.

The primary endpoint is the number of participants with treatment-emergent adverse events and serious adverse events in Part A. The registry specifies a timeframe from Day 1 up to Week 52 and says the safety set includes all participants who received at least 1 dose of study drug. The endpoint is reported as a count of participants, rather than as a measure of change in a clinical score or as a time-to-event estimate.

In general, counts of participants with safety events are used to summarize how many people in a treated population experienced events during a defined observation period. Reporting serious events separately from other adverse events can distinguish events according to their seriousness classification, while still leaving questions about timing, duration, recurrence, and attribution unresolved unless those details are also reported.

The posted Part A summary lists 26 participants with serious adverse events among 172 at risk, and 127 participants with other adverse events among 172 at risk. These are descriptive counts. The record does not report a statistical test, confidence interval, or causal assessment for the primary endpoint. It also does not provide a detailed operational definition of treatment-emergent events in the outcome description. Accordingly, the endpoint helps describe the safety experience recorded during follow-up, but does not alone determine whether an event was caused by study treatment or how the event frequency compares with another treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count show?

The primary outcome is a count of participants with treatment-emergent adverse events and serious adverse events. For Part A, the record lists 172 participants at risk for each event grouping, with 26 participants recorded for serious adverse events and 127 for other adverse events. Part B lists 50 at risk for each grouping, with 8 participants recorded for serious adverse events and 47 for other adverse events. These are counts, not rates per unit of person-time. The registry does not report how long each participant contributed observation time or whether participants had different follow-up durations.

In general, a count tells how many people were recorded as having an event in the defined population. A count does not reveal how often events recurred in the same person, how long they lasted, or when they began. It also does not, by itself, distinguish events caused by treatment from events that occurred while participants were receiving treatment. Those questions require additional definitions and analyses, which are not reported in the registry record.

Why does the study structure matter?

The registry describes a single-group, open-label extension, with no masking and allocation listed as not applicable. In general, a randomized comparison can help separate treatment differences from differences in the participants assigned to each group. Here, the record explicitly cautions that the arms are not a like-for-like control comparison. The posted Part A and Part B summaries are not a substitute for a randomized control group. Differences between their counts cannot be assigned to treatment duration or another cause based on the information available.

Open-label means that masking is not used, as reflected by the record’s masking entry of none. In general, awareness of treatment can affect how symptoms are noticed, reported, or assessed. This possibility is relevant when reading safety summaries, but the record does not report whether or how this may have affected event ascertainment in this study.

What is the role of the safety set?

The safety set includes participants who received at least 1 dose of study drug. This population is used to summarize events among participants exposed to study treatment, according to the registry’s definition. The outcome description applies this population to the primary safety endpoint. The posted at-risk counts are 172 for both event groupings in Part A and 50 for both groupings in Part B.

In general, the population used for a safety analysis should match the question being asked. A safety set focuses on those who were exposed, while other analysis populations can be defined for different questions. The record does not report additional analysis-population definitions or explain how any participants were handled if they had incomplete follow-up.

How should the event terms be read?

The registry lists several top serious adverse-event terms and percentages. The listed terms include infective pulmonary exacerbation of cystic fibrosis at 10.0%, cholecystitis at 2.0%, limb traumatic amputation at 2.0%, forced expiratory volume decreased at 2.0%, productive cough at 2.0%, and alanine aminotransferase increased at 1.2%. These are term-level summaries, distinct from the overall participant counts. The record does not report the denominator, event-coding conventions, or whether a participant could contribute to more than one term in this listing. The terms should therefore be read as the registry’s reported descriptions, not as an exhaustive account of all safety outcomes.

What can statistical uncertainty add?

No confidence intervals or hypothesis-test results are reported for the posted safety counts, and the registry lists no analyses. In general, confidence intervals express uncertainty around an estimate under the assumptions of a specified statistical method. They do not remove design limitations, and they do not turn a single-group description into a controlled comparison. Without such intervals, the record does not quantify the sampling uncertainty around its participant counts.

In general, event data can also vary more than a simple statistical model expects, a property called over-dispersion. This matters when a method assumes a particular level of variability: if the actual data are more variable, standard errors and resulting intervals or tests may be misleading unless the analysis accounts for that variability. The registry record does not report a model for the event counts, a dispersion assessment, or an adjustment for over-dispersion. No claim about the use or suitability of such methods can be made from the posted results.

How do planning illustrations differ from observed results?

The sample-size section is a planning illustration based on the observed effect, using the assumptions described with that section: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is expressed there as a stated fraction of the observed effect. These are planning assumptions, not a description of the study’s own design or its observed analysis.

In general, a planning calculation asks how many participants per arm would be needed to detect an effect under specified assumptions. It does not show that a study had a particular probability of finding a result after the fact. The displayed values are not observed power and should not be read as evidence that this study was adequately or inadequately powered. The sample-size justification for the trial is not reported in the registry record, and the posted results do not provide a randomized two-arm comparison for the planning calculation to reproduce.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan describing how multiple endpoints or event terms were handled. It lists two outcome measures and identifies the Part A adverse-event count as the primary endpoint, but no analysis results are listed. Whether formal multiplicity adjustments were planned or used is not reported in the registry record. The same applies to any prespecified hierarchy among outcomes or adverse-event categories.

Missing-data handling is also not reported in the registry record. The safety set is defined as participants who received at least 1 dose of study drug, and the primary outcome timeframe is from Day 1 up to Week 52. However, the record does not explain how participants with incomplete follow-up were handled, whether event status was available for everyone through that timeframe, or whether any imputation procedure was used. It does not report reasons for missing observations or withdrawals in the information.

The record provides Part A and Part B safety counts, but does not define additional analysis populations or specify an analysis population for a comparative effect estimate. The listed safety set gives a clear exposure-based inclusion rule for the primary endpoint, but other population definitions are not reported in the registry record. No adjusted models, sensitivity analyses, or subgroup analyses are listed. As a result, the posted counts can be described as registry safety summaries, but the assumptions behind any broader statistical analysis cannot be evaluated from this 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 (10.0%), cholecystitis (2.0%), limb traumatic amputation (2.0%), forced expiratory volume decreased (2.0%), productive cough (2.0%).

The serious adverse-event figures are participant counts, not a measure of event frequency per unit of time. Part A lists 26 participants with serious adverse events among 172 at risk; Part B lists 8 among 50 at risk. The registry also reports zero deaths in each part. These values describe the posted summaries and do not establish a treatment effect or a comparison between parts.

The record lists infective pulmonary exacerbation of cystic fibrosis at 10.0% among the top serious adverse-event terms. It also lists cholecystitis, limb traumatic amputation, forced expiratory volume decreased, and productive cough at 2.0% each, and alanine aminotransferase increased at 1.2%. The record does not provide the denominator or detailed calculation method for these term percentages in the summary. They should be read as reported term-level percentages, not combined with one another.

In general, a serious adverse event is a classification of event seriousness, while an overall adverse-event count may include events that do not meet that classification. The registry’s separate grouping of serious and other events should be read according to its labels. The posted results do not establish causation, event duration, recurrence, or whether each event was considered related to treatment.

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

The record shows that safety events were reported among participants receiving study drug in an open-label extension. For Part A, the registry lists 26 participants with serious adverse events and 127 with other adverse events, with 172 at risk in each grouping. For Part B, it lists 8 participants with serious adverse events and 47 with other adverse events, with 50 at risk. No deaths are listed in either part. These counts, along with the serious-event terms, describe the results posted in the registry.

They do not show how the same participants would have fared under another treatment or without study treatment. The study is listed as single-group, and the record says the arms are not a like-for-like control comparison. Part A and Part B should not be treated as randomized groups, and the record does not explain whether the participant groups overlap or have comparable follow-up. Consequently, their counts cannot establish that one part had a safer or less safe experience than the other.

The results also do not establish that study treatment caused an event, or that an event was unrelated to treatment. The posted summaries do not report causal assessments, confidence intervals, hypothesis tests, or adjusted estimates. In general, the absence of a reported event in a summary does not prove that the underlying risk is absent; interpretation depends on the population observed, duration of follow-up, event definitions, and completeness of recording.

The appropriate conclusion is limited: the registry records the specified adverse-event counts in the safety summaries for this study. It does not provide a controlled estimate of comparative safety, a statistical measure of precision, or a complete causal interpretation. These limitations concern what can be inferred from this record; they do not negate the descriptive information it contains.

13. Why This Trial Matters Statistically

This trial matters statistically because safety results from an extension study answer a different question from results in a randomized comparison. The registry describes an open-label, single-group study and posts participant counts for serious and other adverse events. Those data can document events observed among participants receiving treatment, while the design does not provide a like-for-like control comparison.

That distinction is important when interpreting Part A and Part B. Both parts have posted counts, but the record does not report whether participants overlap or whether their follow-up is comparable. A simple comparison of the two summaries would therefore risk treating unlike groups as if they were randomized arms. The registry itself cautions that the arms are not a like-for-like control comparison.

The endpoint also illustrates why the analysis population and observation period matter. The safety set includes participants who received at least 1 dose, and the primary endpoint is framed over a specified period from Day 1 up to Week 52. The posted outcome is a count of participants, while the record does not provide person-time, event recurrence, or a statistical uncertainty estimate. Reading those details together helps separate what is actually summarized from what would require additional data or analyses.

Finally, the record lists adverse-event terms as well as overall participant counts. These summaries can provide context about the types of serious events recorded, but the term percentages do not replace information about causality, timing, or a comparator. The statistical value of the record lies in its descriptive safety information and in the clear limits of the design: it supports characterization of observed events, not a controlled estimate of comparative treatment effects.

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 absence of a like-for-like control comparison. The study is listed as single-group, open label, with allocation not applicable and masking none. The registry explicitly notes that the arms are not a like-for-like control comparison. As a result, the posted counts cannot isolate treatment effects from other explanations for events.

The record gives separate Part A and Part B safety summaries, but does not describe whether the participants overlap, how participants entered Part B, or whether the observation periods are comparable. Part A treatment is described as lasting 48 weeks, Part B treatment as continuing up to 86 weeks, and the primary endpoint timeframe as Day 1 up to Week 52. These descriptions do not establish equivalent follow-up across the posted groups.

The outcome description does not give a detailed definition of treatment-emergent events, and the posted results do not include confidence intervals, hypothesis tests, or analysis results. The record also does not report the denominator or calculation method for the listed percentages of serious adverse-event terms. Event attribution, timing, recurrence, and duration are not included in the summaries.

Further details about missing-data handling, multiplicity, interim analyses, and the sample-size justification are not reported in the registry record. These omissions limit assessment of the analysis plan and the precision of the estimates. The limitations do not change the reported counts, but they constrain how far those counts can be generalized or interpreted causally.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study Evaluating the Long-Term Safety of Elexacaftor Combination Therapy — NCT04362761.
• Registry record last updated 2023-07-28; status last verified 2023-07.
• Results first posted 2023-07-28.
• 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 3b study evaluated the long-term safety and tolerability of elexacaftor/tezacaftor/ivacaftor in participants with cystic fibrosis who are homozygous for F508del. The registry describes an open-label extension, with a single-group model, no masking, and allocation listed as not applicable. It reports an enrollment of 172.

The primary endpoint is the Part A count of participants with treatment-emergent adverse events and serious adverse events from Day 1 up to Week 52. The safety set includes participants who received at least 1 dose of study drug. Part A lists 26 participants with serious adverse events and 127 with other adverse events among 172 at risk; Part B lists 8 and 47, respectively, among 50 at risk. No deaths are listed in either part.

The registry does not report analyses, confidence intervals, or a like-for-like control comparison. The counts therefore provide a descriptive account of reported safety events, not a causal or comparative estimate.