Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age (NCT03691779), a non-randomized phase 3 study. The primary outcome is Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA.

2. Clinical Question

The study evaluated pharmacokinetics, safety, tolerability, efficacy, and pharmacodynamic effects of triple-combination therapy in children with cystic fibrosis. The primary endpoint was the maximum observed plasma concentration of ELX, TEZ, and IVA in Part A on Day 15. Part B included additional outcomes, including lung function, sweat chloride, and a respiratory-domain questionnaire score. The registry record does not report numerical results for the primary endpoint or analyses of the listed outcomes, so the clinical question cannot be answered from reported estimates in the record.

3. Trial Design

This was a Phase 3 study of triple-combination therapy in children 6 through 11 years of age with cystic fibrosis. The registry lists the study as completed, with a recorded enrollment of 71. Its allocation is described as non-randomized, its masking as none, and its model as sequential. These features mean that the record does not describe a blinded randomized comparison of treatment groups. The registry record does not report a control comparison suitable for interpreting differences as randomized treatment effects.

The study had two described parts. In Part A, participants received ELX 100 milligrams once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours during a treatment period of 15 days. Part A focused on pharmacokinetics, with the primary endpoint measured on Day 15. The Part A safety group lists 16 participants at risk for serious and other adverse events.

In Part B, participants weighing less than 30 kilograms at Day 1 received ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours. Participants weighing 30 kilograms or more at Day 1 received ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours. The treatment period was 24 weeks. Part B outcomes included absolute change in percent predicted forced expiratory volume in 1 second, sweat chloride, and the Cystic Fibrosis Questionnaire Revised respiratory-domain score. The Part B safety group lists 66 participants at risk.

The registry record gives the study start as 2018-10-02 and primary completion as 2020-08-07. It does not report how sequential enrollment was organized in detail, why the sample size was selected, or a statistical plan for comparing treatment groups. The posted results contain no analyses for the listed outcome measures.

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 6 through 11 years of age who were homozygous for F508del (F/F) genotype or heterozygous for F508del and a CF transmembrane conductance regulator gene (CFTR) minimal function mutation (F/MF) genotypes.

Part A (15 Days)

Part B (24 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) set for Part A included all participants who have received at least 1 dose of study drug in Part A. Here, the "number analyzed" signifies participants who were evaluable at the specified time point. This outcome measure was planned only for Part A arm.

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: The analysis population included all enrolled participants who carry the intended CFTR allele mutation and received at least 1 dose of study drug in the respective part of the study.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Maximum Observed Plasma Concentration (Cmax) of ELX, TEZ, and IVA, measured over Part A: Day 15.

The primary endpoint is the maximum observed plasma concentration, or Cmax, of ELX, TEZ, and IVA in Part A on Day 15. Concentration is expressed in micrograms per milliliter (mcg/mL). Cmax describes the highest measured plasma concentration over the relevant sampling period. Pharmacokinetic measures such as this help characterize drug exposure; they are not, by themselves, measures of clinical benefit.

The registry specifies that the endpoint is summarized as a mean with standard deviation. The mean describes the average concentration among participants with evaluable measurements. The standard deviation describes how dispersed individual measurements are around that average. Both quantities are useful: a mean alone does not show how similar or different participants' concentrations were.

The Part A pharmacokinetic set included participants who received at least one dose of study drug in Part A. For the endpoint, the registry clarifies that the number analyzed refers to participants evaluable at the specified time point. The outcome was planned only for the Part A arm. The registry record does not report the mean, standard deviation, or number analyzed for this endpoint. It therefore does not permit an assessment of the observed concentration level, its variability, or the precision of an estimated mean.

Concentration measurements depend on the study's sampling schedule and the time at which samples are collected. The registry record does not report the detailed sampling schedule, assay information, or handling of measurements that were unavailable or unevaluable. Those omissions limit the ability to assess the measurement process from the record alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary endpoint as a continuous pharmacokinetic measure summarized by a mean and standard deviation. The posted record does not give the endpoint values or an analysis. The explanations below describe general statistical concepts relevant to this endpoint and the study structure; they should not be read as claims about analyses actually performed.

What does a mean describe?

For a continuous measure, the mean is a way to summarize the central level of observed values. In this study, the target measure was maximum observed plasma concentration on Day 15 in Part A. A mean can make a group-level concentration easier to describe, but it does not show every participant's value. It also does not show whether the measurements cluster closely or vary substantially. A reported mean must be interpreted alongside the number of evaluable observations and a measure of uncertainty or spread.

What does the standard deviation add?

The standard deviation describes the spread of observations around the mean. A smaller spread indicates values are more closely clustered around the average; a larger spread indicates greater variation among observed values. This is a description of individual-level variability, not a measure of how precisely the mean has been estimated. Precision depends in part on the amount of information available, including the number of evaluable participants. The registry record does not report the Part A mean, standard deviation, or number analyzed, so neither the concentration level nor its observed spread can be assessed.

How is precision different from variability?

A confidence interval is a general statistical tool for expressing uncertainty around an estimate. It gives a range of values compatible with the data and analysis under the method's assumptions. A narrow interval generally indicates greater precision than a wide interval, but interpretation depends on the analysis and the quantity being estimated. A confidence interval for a mean is not the same thing as the standard deviation: one concerns uncertainty in the group estimate, while the other describes dispersion among observations. No confidence interval is reported for the primary endpoint in the registry record.

Why does the design affect interpretation?

Random allocation is a general way to balance both measured and unmeasured characteristics between comparison groups, on average. This study is listed as non-randomized, unmasked, and sequential. Those labels do not establish that a controlled comparison was made. When groups are not randomized, differences in their characteristics or the way they enter the study can complicate comparisons. When masking is absent, knowledge of treatment may affect some aspects of measurement or reporting. These are general concerns; the registry record does not describe a randomized comparison or report an adjusted analysis that addresses them.

Sequential models can describe how study parts proceed in sequence, but the registry record does not give further operational details. No assumptions about enrollment order, dose escalation, or decisions between parts should be inferred from the word “sequential” alone. The arm descriptions state that Part A lasted 15 days and Part B lasted 24 weeks; the record does not report how the parts were linked at the participant level.

What can adverse-event counts show?

Adverse-event counts describe the number of participants recorded with events in the relevant safety group. Serious and other adverse events are separate categories in the registry. A serious adverse event is not interchangeable with an event that is merely common, and an “other” event count should not be interpreted as a count of serious events. Descriptive counts do not by themselves establish causation. In this non-randomized record, the figures should not be treated as a controlled estimate of excess risk.

Over-dispersion is a general statistical issue that arises when variation in count data is greater than a chosen model expects. It can make standard errors and confidence intervals from a simple model too optimistic if not handled appropriately. The registry record does not report a count model, an over-dispersion assessment, or an inferential analysis of adverse-event counts. It would therefore be inappropriate to attribute a particular model or correction to this study.

What do the planning assumptions mean?

The registry describes a planning illustration based on the observed effect, using 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. Such an illustration concerns hypothetical future sample-size planning; it is not an observed analysis and is not “observed power.” It does not establish that these assumptions governed the trial's own design. The registry record does not report the trial's sample-size justification or a numerical planning result. The observed endpoint estimate needed to interpret an effect-based illustration is also not reported in the record.

For a general planning calculation, the chosen effect, variability, significance level, allocation, and power target all influence the resulting sample size. If an assumed effect is smaller, more information may be needed to detect it under otherwise comparable assumptions. These are general relationships, not a reconstruction of the study's design. The planning assumptions listed in the registry cannot replace a protocol-level statistical analysis plan.

What is not documented?

The registry record does not report the statistical test used for the primary endpoint, confidence intervals, adjustment for covariates, rules for excluding or transforming observations, or a multiplicity strategy. It also does not report how missing measurements were handled. These details matter because the method of analysis affects the estimate, its uncertainty, and the scope of any statistical conclusion. Without them, the primary endpoint can be described from its definition, but not independently evaluated as a completed analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 23 outcome measures, including the primary Part A Cmax measure and secondary pharmacokinetic, safety, lung-function, sweat-chloride, and questionnaire outcomes. It reports zero analyses. No statistical plan for handling multiple outcomes is reported in the registry record. Multiplicity is a general concern when many outcomes or comparisons are examined: repeated testing can increase the chance of at least one apparently unusual result. Whether and how that concern was addressed cannot be determined from the record.

The registry record does not report how missing data were handled for the primary endpoint or secondary outcomes. It does not describe imputation, exclusion rules, sensitivity analyses, or reasons for missing measurements. The Part A endpoint definition says the “number analyzed” refers to participants evaluable at the specified time point, but gives no numerical number analyzed. The Part A pharmacokinetic set included participants who received at least one dose of study drug in Part A. Details of an analysis population for Part B are not reported in the registry record.

These distinctions matter. The number enrolled, the number who received treatment, and the number with evaluable data for a particular endpoint need not be the same; the record does not give all those counts for each outcome. No further count should be inferred from the enrollment figure or safety denominators. Without documented missing-data methods and endpoint-specific analysis populations, the completeness and representativeness of the analyzed measurements cannot be assessed.

The registry also does not report a statistical analysis plan, interim-analysis procedures, or a sample-size justification. The planning assumptions described for an illustration do not establish the study's own design or analysis choices.

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: metapneumovirus infection (1.5%), pneumonia (1.5%), rhinovirus infection (1.5%).

The registry lists serious adverse events separately from other adverse events. In Part A, 0 participants are listed with a serious adverse event among 16 at risk; 12 are listed with other adverse events among 16 at risk. In Part B, 1 participant is listed with a serious adverse event among 66 at risk; 62 are listed with other adverse events among 66 at risk. The record lists 0 deaths in each part.

The serious adverse-event terms reported are metapneumovirus infection, pneumonia, and rhinovirus infection, each at 1.5%. The registry record does not give additional event-level detail or establish whether these events were considered related to treatment. The listed terms should be read as reported safety findings, not as evidence of a causal relationship.

These figures are descriptive. Because the study is non-randomized and does not report a like-for-like control comparison, they do not establish comparative safety or a treatment-attributable risk. The different group sizes and treatment periods also mean the counts should not be treated as a direct comparison of event rates. The registry record does not report an adjusted safety analysis or time-at-risk analysis. Counts of participants with events are not necessarily counts of all event occurrences, and the record does not provide a total number of events for each category.

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

The registry record establishes that a Phase 3 study evaluated ELX/TEZ/IVA in children with cystic fibrosis, with a Part A pharmacokinetic endpoint and safety monitoring, alongside Part B outcomes that included lung function, sweat chloride, and a respiratory questionnaire score. It also describes treatment schedules and records safety counts. These details convey what was intended to be studied and the broad structure of the study.

However, the record does not report numerical results for the primary Cmax endpoint or analyses for the listed outcomes. It therefore does not show the average Day 15 concentration, the variation in measurements, or the precision of an estimated mean. Nor does it provide outcome estimates for the Part B measures. The description that the study evaluated efficacy or pharmacodynamic effects does not indicate what those measures showed.

The study was non-randomized, unmasked, and sequential. The registry record does not describe a randomized control group or a like-for-like comparison. As a result, the listed safety counts cannot be interpreted as a comparison against an untreated or alternative-treatment group, and they do not establish that treatment caused or prevented an event. The record also does not support a causal conclusion about changes in clinical outcomes.

The absence of reported numerical analyses should not be interpreted as evidence that an outcome was unchanged or that no event occurred. It means that the registry record does not report the relevant estimate. Likewise, a study's completion status does not substitute for results. The findings that can be stated are limited to the endpoint definitions, study design, treatment descriptions, and descriptive safety information entered in the record.

Overall, the record is informative about the study's scope but insufficient for estimating pharmacokinetic values, clinical outcome changes, or comparative safety. Those questions require reported outcome data and methods. No medical conclusion should be drawn from the absence of analyses in the registry record.

13. Why This Trial Matters Statistically

This study is statistically notable for the difference between its broad objectives and the information available for analysis. The registry describes pharmacokinetics, safety, tolerability, efficacy, and pharmacodynamic effects, but the posted record gives no numerical analyses for the listed outcomes. This distinction is important: an outcome named in a registry is not itself a result. Readers need estimates and information about uncertainty to evaluate what the data indicate.

The primary endpoint is a continuous pharmacokinetic measure, summarized by a mean and standard deviation. That pairing addresses two different features of the data: the average concentration and the spread among observations. Yet neither statistic is reported, and the endpoint-specific number analyzed is also absent. The study's central pharmacokinetic question therefore cannot be assessed from the registry record.

The non-randomized, unmasked, sequential design is also relevant. It makes the study description different from a randomized comparative trial, and the record does not provide a like-for-like control comparison. A careful statistical reading must distinguish descriptive observations from estimates of comparative treatment effects. The same caution applies to adverse-event counts: they offer a record of reported safety findings, but not a causal comparison.

Finally, the registry identifies many outcomes without reporting analyses or a multiplicity strategy. In studies with multiple outcomes, the analysis plan helps readers understand which questions were prioritized and how uncertainty was handled. The absence of that information limits interpretation, even when the outcome definitions are clear. This case illustrates why trial design, endpoint reporting, analysis populations, and statistical methods all matter alongside a study's title and completion status.

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 principal limitation for interpreting this record is the absence of numerical results for the primary endpoint. The mean Cmax, standard deviation, number analyzed, and any measure of precision are not reported in the registry record. The record also lists zero analyses for its 23 outcome measures. As a result, the stated pharmacokinetic and clinical questions cannot be evaluated using reported outcome estimates.

The study is identified as non-randomized, unmasked, and sequential, and the record does not describe a randomized control comparison. It therefore does not support a like-for-like comparative treatment estimate. The registry record also does not report whether analyses adjusted for participant characteristics or other factors.

Population details are incomplete for interpreting endpoint-specific data. The Part A pharmacokinetic set is defined, and its number analyzed is said to mean participants evaluable at the specified time point, but the actual number analyzed is not reported. Part B analysis-population definitions are not reported in the registry record. Missing-data handling, exclusions, and sensitivity analyses are also not reported.

The record does not describe a multiplicity strategy, primary-endpoint statistical test, confidence intervals, interim analyses, or the study's sample-size justification. Nor does it provide detailed pharmacokinetic sampling or assay information. These omissions prevent an independent assessment of analysis choices and measurement procedures. The planning illustration assumptions do not fill these gaps or establish how the trial itself was designed.

Safety reporting is descriptive and does not include a controlled comparison or a reported analysis of time at risk. The registry does not give further event-level detail or an attribution analysis. These limits are specific to the information recorded and should not be taken to imply that unreported analyses or details were not collected elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of VX 445/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age — NCT03691779.
• Registry record last updated 2021-10-22; status last verified 2021-08.
• Results first posted 2021-10-22.
• 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

NCT03691779 is a completed Phase 3 study of VX-445/TEZ/IVA triple-combination therapy in children 6 through 11 years of age with cystic fibrosis. The registry lists a non-randomized allocation, no masking, and a sequential model, with enrollment of 71. Part A evaluated pharmacokinetics and safety over 15 days; Part B evaluated treatment over 24 weeks, with doses based on weight at Day 1.

The primary endpoint was mean maximum observed plasma concentration of ELX, TEZ, and IVA on Day 15 in Part A, with standard deviation as the dispersion measure. The registry record lists 23 outcome measures and zero analyses, and does not report numerical primary-endpoint results. Safety entries include serious and other adverse-event counts, listed serious-event terms, and no deaths recorded in either part. The record does not describe a randomized control comparison or report the statistical plan, missing-data methods, or multiplicity strategy.