Evaluation of ELX/TEZ/IVA in Cystic Fibrosis (CF) Subjects 2 Through 5 Years: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of ELX/TEZ/IVA in Cystic Fibrosis (CF) Subjects 2 Through 5 Years (NCT04537793), a non-randomized phase 3 study. The primary outcome is Part A: Observed Pre-dose Concentration (Ctrough) of ELX,TEZ,IVA, and Relevant Metabolites.

2. Clinical Question

The study is titled as an evaluation of ELX/TEZ/IVA in children aged 2 through 5 years with cystic fibrosis. Its stated objectives include safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy. The posted primary outcome focuses specifically on pre-dose concentrations in Part A. Secondary outcomes listed for Part B include pre-dose concentrations, absolute change in sweat chloride, and absolute change in lung clearance index 2.5.

The registry record does not report numerical results for the primary endpoint or the listed secondary outcomes. It therefore does not support a quantitative account of the observed concentration levels or changes in those measures. The study structure also does not support treating one group as a randomized control for the other. Its design and endpoint can describe drug exposure and safety in the enrolled study population, but they do not by themselves establish a causal treatment effect relative to a control.

3. Trial Design

This was a phase 3 study with nonrandomized allocation, no masking, and a sequential model. The registry record gives an enrollment of 83 and lists cystic fibrosis as the condition. It identifies ELX/TEZ/IVA and ivacaftor as drug interventions. Because allocation was nonrandomized, the treatment groups should not be read as equivalent groups created by random assignment; the record itself cautions that the arms are not a like-for-like control comparison.

The study description divides treatment into Part A and Part B. In Part A, participants weighing at least 14 kg at screening received ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours during a 15-day treatment period. In Part B, participants at least 14 kg received the same listed doses, while participants weighing at least 10 kg but less than 14 kg received ELX 80 mg once daily, TEZ 40 mg once daily, and IVA 60 mg each morning and 59.5 mg each evening. Part B treatment lasted 24 weeks.

The primary outcome is a pharmacokinetic measure in Part A: observed pre-dose concentrations of ELX, TEZ, IVA, and relevant metabolites from Day 1 through Day 15. The registry describes the measure as a mean with standard deviation. Its stated analysis population is the pharmacokinetic set, defined as participants who received at least one dose; the number analyzed at a specified time point means the participants evaluable at that time point.

The registry also lists Part B outcomes for pre-dose concentrations, absolute change in sweat chloride, and absolute change in lung clearance index 2.5. No numerical results for these outcomes are reported in the registry record. The record does not report the rationale for the sequential structure, the method used to assign participants to parts, or a detailed statistical analysis plan. Those features should not be inferred from the dosing descriptions alone.

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 participants with cystic fibrosis (CF) aged 2 through 5 years of age (inclusive).

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 included participants who received at least 1 dose of study drug. Here the "Number Analyzed" signifies those participants who were evaluable at specified time point.

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: All participants who received at least one dose of the study drug during the treatment period were included in the baseline analysis.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Observed Pre-dose Concentration (Ctrough) of ELX,TEZ,IVA, and Relevant Metabolites, measured over From Day 1 through Day 15.

The primary endpoint is the observed pre-dose plasma concentration, or Ctrough, of ELX, TEZ, IVA, and relevant metabolites. The registry gives the unit as micrograms per milliliter and the timeframe as Day 1 through Day 15 in Part A. It specifies a mean and standard deviation as the summary measures.

In general, a pre-dose concentration describes the amount of a drug or metabolite measured before a scheduled dose. Pharmacokinetic measurements are used to characterize drug exposure over a dosing period. A mean summarizes the central level across observed measurements, while a standard deviation describes how spread out those measurements are around the mean. These summaries can help characterize exposure in the study population, but do not on their own indicate whether a treatment improves health outcomes or how it compares causally with another treatment.

The registry record defines the pharmacokinetic set as participants who received at least one dose of study drug. At each specified time point, the number analyzed refers to those evaluable at that time point, so the contributing participants may vary across measurements. The record does not report the numerical concentrations, standard deviations, or numbers analyzed at the time points. As a result, the magnitude and precision of the observed concentration summaries cannot be assessed from the registry record.

Part B also lists sweat chloride and lung clearance index 2.5 outcomes, but these are secondary measures, not the stated Part A primary endpoint. Their numerical results are not reported in the registry record either.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a continuous primary outcome summarized as a mean and standard deviation. It does not report numerical primary-endpoint estimates, confidence intervals, hypothesis tests, or a detailed statistical plan. The concepts below explain how these methods are generally interpreted; they do not imply that an unreported analysis was performed.

What does a mean describe?

In general, the mean is a measure of the central value of a set of observations. For the stated primary endpoint, it would describe the average observed pre-dose concentration among participants with an evaluable measurement at a specified time point. It can provide a concise summary, but it does not show the full distribution. A mean can be influenced by unusually high or low observations, and a similar mean can arise from different patterns of individual measurements.

The registry specifies the number analyzed at each time point as the participants evaluable at that time point. That definition matters because an analysis may include fewer participants at some measurements than others. The record does not give the time-point-specific counts or concentration means, so the actual pattern cannot be reconstructed from the registry information.

What does a standard deviation describe?

In general, a standard deviation describes the spread of observations around their mean. A smaller standard deviation indicates that observations are more tightly clustered around the mean; a larger one indicates greater dispersion. It is not the same as a confidence interval. A standard deviation describes variability among observations, while a confidence interval describes uncertainty about an estimated quantity under a statistical model.

The primary endpoint is reported as a mean with standard deviation in its definition, but the actual values are not reported in the registry record. Readers therefore cannot judge the observed variability or use it to assess how representative the mean might be of individual participants.

What is a confidence interval?

In general, a confidence interval gives a range of values compatible with the observed data under the assumptions of the analysis method. It is often used to express the precision of an estimate. A narrower interval generally indicates more precision than a wider interval, though precision does not establish that an estimate is unbiased or that a treatment has a causal effect. The registry record does not report a confidence interval for the primary endpoint.

A p-value, in general, quantifies how unusual the observed data would be under a specified null hypothesis and statistical model. It does not measure the size or importance of an effect, and it is not the probability that a hypothesis is true. No primary-endpoint p-value is reported in the registry record. The record also does not report a hypothesis-testing plan, so no inferential procedure should be assumed.

Why does the study design matter for inference?

In general, randomization is a design method for assigning participants to groups in a way that can reduce systematic differences between them. This study is identified as nonrandomized, unmasked, and sequential. Consequently, the listed treatment groups should not be interpreted as randomized comparison groups. An unmasked design also means the record does not describe masking intended to keep participants or study personnel unaware of treatment assignment. The registry does not report further details about how assignment occurred or how awareness was managed.

Because the study is sequential, results from the different parts should be interpreted according to their own populations, treatment schedules, and endpoint timeframes. Part A supplies the primary pharmacokinetic endpoint and has a 15-day treatment period. Part B has a 24-week treatment period and lists secondary outcomes. In general, differences between sequential groups can be entangled with differences in eligibility, timing, dose, or participant characteristics. The record does not establish that these factors were controlled in a comparative analysis.

How should the planning illustrations be understood?

The planning illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They are described as illustrations computed from an observed effect, with the target effect defined as a stated fraction of that observed effect. For non-time-to-event outcomes, the requested quantity is participants per arm; time-to-event illustrations use a total number of events. These are planning assumptions, not evidence that the trial was designed with those assumptions or that it achieved a particular power.

In general, a sample-size calculation estimates the amount of information needed to detect a specified effect under stated assumptions. It is not an observed result and does not show whether an effect was actually detected. The registry record does not report the trial's own sample-size justification, its planned statistical power, or a statistical analysis plan. No sample-size estimate should be interpreted as observed power.

What does over-dispersion mean in general?

Over-dispersion occurs when observed variability is greater than a statistical model expects. In general, ignoring excess variability can make standard errors too small and confidence intervals too narrow, leading to overly optimistic precision. Its relevance depends on the outcome and model. The stated primary endpoint is continuous and summarized by a mean and standard deviation; the registry does not report a model or an over-dispersion assessment. It would therefore be inappropriate to claim that over-dispersion was present, absent, or adjusted for in this study.

These general concepts help distinguish what the endpoint definition tells readers from what numerical results and analysis details would be needed for a full statistical assessment. The registry record does not report those primary-endpoint results or the detailed methods needed to evaluate them.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures and no analyses. It identifies one primary outcome: Part A observed pre-dose concentrations of ELX, TEZ, IVA, and relevant metabolites. It also lists secondary Part B measures for pre-dose concentrations, absolute change in sweat chloride, and absolute change in lung clearance index 2.5. Numerical results for these measures are not reported in the registry record.

Multiplicity arises in general when several outcomes, time points, or statistical tests are considered. If many tests are conducted, the chance of at least one apparently unusual result can increase. Statistical plans sometimes address this through a prespecified hierarchy or adjustment procedure. The registry record does not report whether multiplicity was considered, whether any adjustment was planned, or which comparisons or time points were intended for formal inference. It is not possible to infer such a plan from the outcome list.

The primary pharmacokinetic analysis population is defined as participants who received at least one dose of study drug. The number analyzed at each time point represents those evaluable at that time point. This definition indicates that the available analysis set can vary by measurement. The registry record does not report how missing or unevaluable measurements were handled, the reasons for missing measurements, or any imputation method. It also does not report whether the analysis included all eligible participants, how protocol deviations were handled, or whether sensitivity analyses were performed.

These omissions limit assessment of the robustness of any estimated outcome. They do not establish that missing data or multiplicity changed a result; the relevant numerical results and analysis details are not reported in the registry 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: anal incontinence (1.3%), infective pulmonary exacerbation of cystic fibrosis (1.3%), abnormal behaviour (1.3%), urinary incontinence (1.3%).

The registry reports serious adverse events for each treatment part. In Part A, 0 of 18 participants at risk were affected by a serious adverse event; in Part B, 2 of 75 were affected. The registry lists other adverse events affecting 15 of 18 participants at risk in Part A and 71 of 75 in Part B. It reports 0 deaths in both parts.

The serious adverse event terms listed with the same reported percentage are anal incontinence, infective pulmonary exacerbation of cystic fibrosis, abnormal behaviour, and urinary incontinence; each is reported as 1.3%. These term-level figures should be read as the registry presents them, not as evidence that the events occurred at equal frequency across treatment parts.

In general, an affected-participant count indicates how many participants had at least one event in the specified category; it is not necessarily the total number of event episodes. The record does not report further detail in the registry record about event duration, severity beyond the serious classification, or participant-level overlap between categories. The group counts are descriptive, not a randomized comparison. The nonrandomized design, different treatment periods, and weight-based dosing descriptions mean that the counts alone cannot establish a comparative safety effect.

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

The registry record establishes that a phase 3 study evaluated ELX/TEZ/IVA in children aged 2 through 5 years with cystic fibrosis. It describes a sequential, nonrandomized, unmasked study with a Part A treatment period of 15 days and a Part B treatment period of 24 weeks. Its primary endpoint is a pharmacokinetic measure: observed pre-dose concentrations of ELX, TEZ, IVA, and relevant metabolites in Part A. The record also lists secondary pharmacokinetic and pharmacodynamic outcomes in Part B.

The endpoint definition tells readers what was measured, in whom, and over what stated timeframe. It does not provide the observed concentration values, their standard deviations, or the number analyzed at each time point. Consequently, the registry record does not allow readers to quantify the observed exposure or assess its statistical precision. The listed secondary outcomes likewise have no numerical results reported in the registry record.

The safety counts are descriptive summaries. They report serious and other adverse events in the two study parts, along with zero deaths in each part. They do not show that one treatment is safer or less safe than another. The study was not randomized, and the registry explicitly cautions against treating the arms as a like-for-like control comparison.

More generally, a pharmacokinetic endpoint can characterize drug exposure, but it is not interchangeable with a clinical outcome. Even a precise concentration estimate would not by itself establish a treatment effect on symptoms, function, or another health outcome. The record does not report the numerical outcome results or inferential analyses needed to assess efficacy. The study description states that efficacy was evaluated, but this does not substitute for posted efficacy results.

The registry record therefore supports a description of the study design, treatment schedules, endpoint definitions, and selected safety counts. It does not support conclusions about the size or precision of primary-endpoint results, the size of changes in the secondary outcomes, or causal differences between treatments. Those distinctions are important when interpreting what the study record can establish.

13. Why This Trial Matters Statistically

This study is statistically notable for the distinction between measuring pharmacokinetic exposure and estimating a comparative treatment effect. Its primary endpoint is a mean pre-dose concentration with standard deviation, a continuous measure intended to describe drug and metabolite exposure. Such an endpoint can answer a different question from whether a clinical outcome improves. Keeping the endpoint's role clear prevents pharmacokinetic summaries from being mistaken for direct evidence of clinical benefit.

The sequential, nonrandomized structure also matters. Comparisons across groups in a nonrandomized study can reflect differences in participants, treatment schedules, or timing as well as treatment itself. The registry record specifically cautions that the arms are not a like-for-like control comparison. This limits the causal interpretation that can be attached to differences between groups, even if numerical results were available.

The study also describes distinct weight-based dosing in Part B and separate treatment durations for the two parts. These features make it important to interpret each part within its own design and endpoint context. They should not be collapsed into a single undifferentiated comparison.

Finally, the registry record illustrates the difference between a study description and a statistical result. It identifies the primary outcome and analysis population, but numerical primary and secondary outcome results are not reported in the registry record. The distinction matters because endpoint definitions alone cannot show the observed magnitude, variability, precision, or clinical relevance of an outcome. The posted safety counts offer descriptive information, while the design limits direct comparative claims.

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 limitation for statistical interpretation is that the registry record does not report numerical results for the primary pharmacokinetic endpoint or the listed secondary outcomes. The primary endpoint is defined as a mean with standard deviation, but the values and time-point analysis counts are not reported. The registry also lists no analyses. This prevents assessment of effect magnitude, variability, precision, or formal statistical evidence for the outcome measures.

The nonrandomized allocation and sequential model limit interpretation of between-group differences. The record cautions that the arms are not a like-for-like control comparison. It does not report enough detail to determine how participants were assigned to parts or whether potential differences between groups were addressed analytically. Masking is listed as none, and the record does not report further information about how this feature affected measurement or reporting.

The parts differ in treatment duration and dosing descriptions, including weight-based dosing in Part B. Part A supplies the stated primary endpoint, while Part B includes secondary outcomes. These differences limit direct comparisons across parts. The registry record does not report the statistical analysis plan, the trial's sample-size justification, interim analyses, or methods for handling missing or unevaluable data. It also does not report whether multiplicity was addressed.

The available safety counts are descriptive and do not establish comparative risks. The record does not provide numerical efficacy results despite listing efficacy among the study objectives. These limitations are specific to the registry information; they do not establish what analyses or results may exist outside the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of ELX/TEZ/IVA in Cystic Fibrosis (CF) Subjects 2 Through 5 Years — NCT04537793.
• Registry record last updated 2023-06-28; status last verified 2023-06.
• Results first posted 2023-06-28.
• 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

NCT04537793 is a completed phase 3 study of ELX/TEZ/IVA in children aged 2 through 5 years with cystic fibrosis. The registry describes nonrandomized allocation, no masking, and a sequential model, with an enrollment of 83. Part A treatment lasted 15 days and Part B treatment lasted 24 weeks, with Part B dosing varying by screening weight.

The primary outcome is the Part A mean pre-dose concentration of ELX, TEZ, IVA, and relevant metabolites, with standard deviation, measured from Day 1 through Day 15. The registry defines the pharmacokinetic set as participants who received at least one dose, with the number analyzed at each time point limited to those evaluable then. Numerical primary and secondary outcome results are not reported in the registry record, and the record lists no analyses.

Safety counts are reported for serious and other adverse events, with 0 deaths in each part. The nonrandomized design means the treatment groups are not a like-for-like control comparison.