Evaluation of VX-659/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-659/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age (NCT03633526), a registered phase 3 study. The primary outcome is Maximum Observed Concentration (Cmax) of VX-659, TEZ, and IVA.

2. Clinical Question

3. Trial Design

This was a Phase 3, sequential study evaluating pharmacokinetics, safety, and tolerability of VX-659/TEZ/IVA in children with cystic fibrosis who were 6 through 11 years of age. The registry also describes efficacy and pharmacodynamic effects among the study objectives. Eligible genotypes named in the record were F/F or F/MF. The study was not listed as randomized; allocation is not stated, and masking was listed as none. These design details do not establish a randomized or blinded comparison.

The registry records enrollment of 18 and lists the study status as terminated. Its brief summary states that the study was discontinued after completion of Part A due to Sponsor's discretion. The start date is 2018-08-03 and the primary completion date is 2019-01-18. The record does not explain the sponsor's decision further, so the reason should not be inferred beyond the stated discretion.

The described triple-combination regimen consisted of a morning fixed-dose combination of VX-659 120 mg/TEZ 50 mg/IVA 75 mg, with IVA 75 mg as a mono tablet in the evening. The record lists IVA separately as an intervention, but the available arm description pertains to VX-659/TEZ/IVA. Allocation and a separate comparator regimen are not reported in the registry record. Accordingly, the design information does not support interpreting the entries as a balanced comparison between treatments.

The primary endpoint was Cmax of VX-659, TEZ, and IVA at Day 1 and Day 15. Secondary outcomes named pharmacokinetic measures for TEZ and IVA metabolites, including Cmax, pre-dose concentration, and area under the concentration-versus-time curve from time 0 to 6 hours, as well as treatment-emergent adverse events and serious adverse events. The registry lists 7 outcome measures and 0 analyses. Specific result estimates for the primary endpoint are not reported in the registry record.

4. Participant Flow and Accounting

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

Before assignment: This study was conducted in participants with cystic fibrosis (CF) 6-11 years of age. The study was terminated before start of Part B at Sponsor's discretion.

Overall Study

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 and for whom the primary PK data were considered to be sufficient and interpretable. Here "Number analyzed" signifies those subjects who were evaluable at the specified timepoint.

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.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Concentration (Cmax) of VX-659, TEZ, and IVA, measured over Day 1 and Day 15.

The primary endpoint is maximum observed concentration, or Cmax, for VX-659, TEZ, and IVA. It is specified in microgram per milliliter (mcg/mL), with measurements on Day 1 and Day 15. In general, Cmax is a pharmacokinetic measure: it describes the highest concentration observed over the relevant sampling period. It can characterize drug exposure, but by itself does not establish clinical benefit, long-term safety, or how a treatment compares with another regimen.

The registry specifies the endpoint summary as a mean with standard deviation. In general, a mean describes the center of a set of measurements, while a standard deviation describes their spread around that mean. Both can help characterize observed concentrations, but interpretation also depends on how many observations contributed, the sampling schedule, and whether measurements were complete and interpretable. The registry defines the pharmacokinetic set as participants who received at least one dose and whose primary pharmacokinetic data were considered sufficient and interpretable. It clarifies that the number analyzed refers to participants evaluable at the specified timepoint.

Primary Cmax estimates, standard deviations, and timepoint-specific analyzed counts are not reported in the registry record. Therefore, the endpoint's definition can be described, but its observed magnitude and precision cannot be assessed from the registry information available in this record. The endpoint is pharmacokinetic rather than a direct clinical outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary endpoint as a continuous pharmacokinetic measure: maximum observed concentration of VX-659, TEZ, and IVA, in microgram per milliliter (mcg/mL), at Day 1 and Day 15. The endpoint summary parameter is a mean, with standard deviation as its dispersion measure. In general, continuous data can take a range of numerical values. A mean offers a concise description of the center of observed values, and a standard deviation describes how dispersed those values are around the mean. These summaries are descriptive; on their own, they do not establish a treatment effect or its precision.

What does Cmax describe?

In general, Cmax is the highest concentration observed during the relevant collection period. It is used in pharmacokinetic assessment to characterize measured drug exposure. Its interpretation depends on when samples were collected and how the observation period was defined. The registry record identifies the Day 1 and Day 15 timepoints, but does not report sampling schedules, the concentration estimates, or additional details about the observation window. Those details are not reported in the registry record and should not be assumed.

How should mean and standard deviation be read?

In general, the mean summarizes the average of the measured values, while the standard deviation describes their spread. A small standard deviation relative to the mean would indicate less variation among observations than a larger one, but the registry provides no endpoint values with which to make that assessment. Standard deviation is not the same as a confidence interval: the former describes variation among measurements, while a confidence interval is used to express uncertainty around an estimated quantity under a specified statistical method. Confidence intervals for the primary endpoint are not reported in the registry record.

The registry defines the pharmacokinetic set as participants who received at least one dose and had primary pharmacokinetic data considered sufficient and interpretable. It also states that the number analyzed signifies participants evaluable at the specified timepoint. This makes the analysis population endpoint- and timepoint-specific. In general, a participant may be included in one timepoint's analysis but not another if data availability or interpretability differs. The record does not report the analyzed count for either primary timepoint, nor does it describe how missing or uninterpretable measurements were handled.

What can a sequential design establish?

The model is listed as sequential, masking as none, and allocation as not stated. In general, sequential designs can involve stages or periods in an ordered sequence, but the registry information does not describe the study's detailed sequence, transitions, or analysis of period effects. No additional protocol structure should be inferred from the label alone. The record does not identify a randomized control comparison, and the listed interventions do not have matching arm descriptions. Therefore, a controlled treatment contrast is not established by the information available.

In an unmasked study, participants and study personnel are not described as blinded to treatment assignment. In general, lack of masking can affect subjective assessments or study conduct, although this pharmacokinetic endpoint is a measured concentration. The registry does not report specific procedures for laboratory assessment, quality control, or masking of assay personnel, so no claims about those procedures are warranted.

What do the planning illustrations mean?

General sample-size planning asks how much information may be needed to detect a specified effect under stated assumptions. The planning illustrations associated with the posted results use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. The record cautions that these are planning illustrations computed from an observed effect, not the trial's own design. It also specifies that time-to-event illustrations report total events, while other illustrations report participants per arm.

Those planning assumptions should not be mistaken for the trial's actual statistical plan or for an observed property of this study. In particular, a planning illustration is not observed power and does not show that the trial was designed with those assumptions. The record does not report the trial's sample-size justification, a prespecified effect used in planning, or the detailed statistical analysis plan. Because primary endpoint estimates are not reported in the registry record, no numerical planning result should be interpreted as a trial finding.

Why does over-dispersion matter in general?

For some outcomes, the observed variability can exceed what a simple statistical model expects. In general, this is called over-dispersion and can make standard errors too small if the analysis does not account for it. That concern is relevant to count outcomes in suitable settings, but the primary endpoint in this record is a continuous concentration measure summarized with a mean and standard deviation. The registry does not report a model for the primary endpoint, an over-dispersion assessment, or an adjustment for it. No particular model should be attributed to the study.

The registry lists 7 outcome measures and 0 analyses. It identifies the primary endpoint and names secondary pharmacokinetic and adverse-event outcomes, but does not report inferential methods, confidence intervals, p-values, covariate adjustments, or model diagnostics. Consequently, the available record supports a description of the planned measurement and population definition, but not a reconstruction of the analysis or a judgment about its statistical adequacy.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies Cmax of VX-659, TEZ, and IVA as the primary endpoint and lists secondary pharmacokinetic and adverse-event outcomes. It reports 7 outcome measures and 0 analyses. The record does not describe a multiplicity procedure, such as an adjustment across endpoints, timepoints, or comparisons, and does not report a detailed statistical analysis plan. Whether results were intended to be tested in a hierarchy or interpreted descriptively is not reported in the registry record.

Missing-data procedures are also not reported. The record defines the pharmacokinetic set as participants who received at least one dose and had primary pharmacokinetic data considered sufficient and interpretable. It says that the number analyzed refers to participants evaluable at a specified timepoint. This definition identifies an analysis population but does not explain how missing samples, measurements outside an interpretable range, or other incomplete data were handled. The numbers analyzed at Day 1 and Day 15 are not reported in the registry record.

In general, missing-data methods matter because estimates can depend on which observations are available and why others are missing. Likewise, multiplicity matters when multiple outcomes or comparisons are assessed, because interpreting many tests can affect the chance of a nominally unusual result. These are general statistical considerations, not claims about what occurred in this study. The registry record does not report interim analyses, imputation methods, sensitivity analyses, or the handling of repeated measurements.

The study was discontinued after completion of Part A due to Sponsor's discretion, according to the brief summary. The registry does not state whether the termination affected the analysis plan or the availability of data. That information is 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: rash (6.2%).

The registry reports safety figures for the VX-659/TEZ/IVA group. Serious adverse events affected 1 participant among 16 at risk. Other adverse events affected 13 among 16 at risk. The reported number of deaths is 0. These are descriptive counts within the listed group; no comparative safety estimate is reported in the registry record. The enrollment entry of 18 is not the denominator used for these specific safety figures.

Rash is listed among the top serious adverse event terms at 6.2%. The registry does not provide additional detail in this record about the event's timing, severity, outcome, or relation to study treatment. The percentage should be read as the registry's listed term value, not as a basis for calculating an unreported rate or comparison.

In general, an adverse event is an event recorded during a study and does not by itself establish that treatment caused it. A serious adverse event is a classification based on seriousness criteria; it is not simply another way to say that an event was common or severe in everyday language. The record does not provide a comparator with a corresponding safety description that would support a like-for-like risk comparison. These counts therefore describe the reported safety experience in the listed group, but do not establish causation or comparative safety.

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

The registry record establishes that this was a Phase 3, sequential study of VX-659/TEZ/IVA in children with cystic fibrosis aged 6 through 11 years, with F/F or F/MF genotypes. It describes a triple-combination regimen and identifies Cmax of VX-659, TEZ, and IVA at Day 1 and Day 15 as the primary endpoint. It also records the study as terminated and states that it was discontinued after completion of Part A due to Sponsor's discretion.

Those details describe the study and its intended measurements; they do not provide the primary endpoint results. Mean concentration estimates, standard deviations, timepoint-specific analysis counts, and confidence intervals are not reported in the registry record. Consequently, the magnitude and precision of observed concentrations cannot be assessed from this record. No treatment effect or efficacy conclusion can be drawn from a primary pharmacokinetic endpoint whose numerical estimates are not reported.

The registry lists serious and other adverse event counts and a death count for the VX-659/TEZ/IVA group. Those figures provide a limited description of the reported events in that group. Without a like-for-like comparator, detailed event information, and a fuller account of follow-up, they do not establish that treatment caused or prevented an event, nor do they quantify comparative risk.

The listed intervention IVA does not by itself create a valid comparator. The record does not describe a corresponding arm, state allocation, or report a randomized treatment contrast. The sequential design label and lack of masking also do not substitute for evidence of a controlled comparison. Interpretation should therefore remain descriptive and specific to the registry entries.

The study's termination is reported, but its cause beyond Sponsor's discretion is not. It should not be interpreted as proof of benefit, lack of benefit, harm, or a particular operational problem. The registry record does not explain whether all intended analyses were completed, and it lists 0 analyses. Overall, the record supports conclusions about the study's stated population, regimen, endpoint definition, status, and limited safety counts, but not a conclusion about efficacy or comparative treatment effects.

13. Why This Trial Matters Statistically

This study is statistically notable because its primary question is pharmacokinetic. Cmax describes an observed concentration rather than a direct clinical outcome. That distinction matters: a concentration endpoint can characterize exposure, but it does not by itself answer whether participants experienced a clinical benefit or how treatment compares with an alternative. The registry's primary endpoint definition is clear, while its numerical estimates are not reported.

The record also illustrates why analysis populations and timepoints need to be read carefully. The pharmacokinetic set includes participants who received at least one dose and had primary data considered sufficient and interpretable, while the analyzed count is timepoint-specific. The registry does not report those counts. Enrollment and safety denominators describe different entries and cannot stand in for the missing timepoint-specific analysis counts.

Design information constrains what can be inferred. The study is described as sequential, with masking none and allocation not stated. The record does not establish a randomized, like-for-like comparison, even though IVA appears in the intervention list. Without a clearly described comparator and comparative results, a causal treatment contrast cannot be recovered from the listed group information.

Finally, discontinuation after Part A and the absence of posted primary estimates make transparent reporting especially important for interpretation. The record states the study was stopped at the sponsor's discretion but does not explain the reason further. It reports safety counts, yet does not provide the primary pharmacokinetic estimates or a statistical analysis description. Statistically, these omissions limit assessment of precision, missing-data effects, multiplicity, and comparative inference. The record can still be read accurately as a description of the planned endpoint and reported safety entries, provided those limits remain explicit.

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 primary limitation for interpreting the main endpoint is that its numerical results are not reported in the registry record. Although the record specifies Cmax, units, timepoints, mean, and standard deviation, it does not provide the mean concentrations, their dispersion, or the number analyzed at either timepoint. Precision and observed concentration patterns therefore cannot be assessed.

The registry lists enrollment of 18, but the safety figures use an at-risk count of 16 for the VX-659/TEZ/IVA group. The record does not explain the relationship between these entries or provide timepoint-specific pharmacokinetic counts. These counts should not be combined or treated as equivalent populations.

The design details limit comparative interpretation. The study is identified as sequential, masking is listed as none, and allocation is not stated. A separate IVA intervention is listed, but a corresponding arm description and like-for-like comparator results are not available. The record therefore does not establish a randomized comparison. The termination after Part A is reported, but the sponsor's further rationale is not reported in the registry record.

Further trial-specific limitations include the absence of a detailed statistical analysis plan, sample-size justification, multiplicity strategy, missing-data procedure, and inferential results in the registry record. The record lists 7 outcome measures and 0 analyses. It does not report interim analyses or explain how the study's discontinuation affected data collection or analysis. These omissions prevent assessment of the intended statistical framework and limit conclusions to the registry's descriptive information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of VX-659/TEZ/IVA in Cystic Fibrosis Subjects 6 Through 11 Years of Age — NCT03633526.
• Registry record last updated 2020-02-05; status last verified 2020-01.
• Results first posted 2020-02-05.
• 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

The registry describes NCT03633526 as a Phase 3, sequential study evaluating VX-659/TEZ/IVA in children with cystic fibrosis aged 6 through 11 years, with F/F or F/MF genotypes. Enrollment is recorded as 18. The study status is terminated, and the brief summary says it was discontinued after completion of Part A due to Sponsor's discretion.

The primary endpoint is maximum observed concentration of VX-659, TEZ, and IVA in mcg/mL at Day 1 and Day 15, summarized as a mean with standard deviation. Primary endpoint estimates and timepoint-specific analyzed counts are not reported in the registry record. Safety entries for the VX-659/TEZ/IVA group report 1 serious adverse event among 16 at risk, 13 with other adverse events among 16 at risk, and 0 deaths. The record lists rash at 6.2% among the top serious terms. Allocation is not stated, masking is none, and a like-for-like control comparison is not established.