Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del (NCT02797132), a na phase 3 study. The primary outcome is Part A: Pre-dose Concentration (Ctrough) of LUM and IVA.

2. Clinical Question

3. Trial Design

This was a Phase 3, two-part, open-label, multicenter study of lumacaftor/ivacaftor in children aged 2 through 5 years with cystic fibrosis who were homozygous for the F508del-CFTR mutation. The registry lists the study as completed and records enrollment of 62 participants. The study started in 2016-05, with primary completion in 2017-09.

Part A focused on pharmacokinetics, safety, tolerability, and pharmacodynamics after multiple doses. Its primary endpoint was pre-dose concentration of lumacaftor and ivacaftor at Day 15. The Part A pharmacokinetic set included participants who received at least 1 dose of the combination therapy in Part A. The registry describes dose groups according to weight at screening, but the full dosing description is not reported in the registry record.

Part B included further evaluation of the combination therapy. The listed secondary outcomes include sweat chloride and measures of body mass index, weight, and stature at Week 24. Participants who took part in Part A could participate in Part B if they met the eligibility criteria; the record does not say that every Part A participant continued.

Because the study was open-label and single-group, it does not provide a randomized comparison with an untreated or alternative-treatment group. The registry’s Part A and Part B dose groups are not randomized control arms. Differences across those groups could reflect their different study parts, dosing, participant characteristics, or eligibility, as well as other factors. The record does not report enough detail to separate those possible influences.

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.

Part A (15 Days)

Reasons for not completing this period:

Part B (24 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The pharmacokinetic (PK) set for Part A included all participants who received at least 1 dose of LUM/IVA in Part A.

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 Safety Set included all participants who received at least 1 dose of LUM/IVA in the respective study part.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Pre-dose Concentration (Ctrough) of LUM and IVA, measured over Day 15.

The primary endpoint was the pre-dose concentration, called Ctrough, of lumacaftor and ivacaftor on Day 15 in Part A. Concentration is expressed in nanograms per milliliter. The planned summary measure was a mean with standard deviation, using the Part A pharmacokinetic set: participants who received at least 1 dose of LUM/IVA in Part A.

In general, a pre-dose concentration is measured near the end of a dosing interval, before the next dose. It is used in pharmacokinetic assessment because it describes drug concentration at a consistent point in the dosing schedule. Such measurements can help characterize exposure during repeated dosing. They do not, on their own, establish a clinical benefit or quantify a change in symptoms or disease status.

The registry lists the endpoint and its measurement time but does not report the mean concentration, standard deviation, or other numerical result for it. It also does not report a confidence interval or a statistical comparison for this endpoint. Consequently, the registry record supports describing what was measured, but not estimating the observed concentration or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary outcome as a continuous measure summarized by a mean and standard deviation. In general, a mean gives the arithmetic center of observed measurements, while a standard deviation describes how spread out those measurements are around the mean. The mean is the planned summary for Day 15 Ctrough concentrations in the Part A pharmacokinetic set. The registry record does not report the numerical mean or standard deviation, so the actual concentration level and observed spread cannot be evaluated.

What does Ctrough represent?

In general, a trough concentration is a measurement taken at the low point of a dosing interval, typically just before the next dose. Repeated measurements at a defined point in a dosing schedule can help characterize pharmacokinetic exposure. A concentration measurement is not the same as a measure of clinical response: it describes drug concentration, not whether a participant experienced a particular health outcome. The registry identifies Day 15 as the primary endpoint timeframe but does not report the observed values or additional collection details.

How should a standard deviation be read?

In general, a standard deviation describes variation among individual measurements in the analyzed group. It is not a confidence interval and does not directly express the precision of the group mean. A confidence interval, when reported, gives a range of values compatible with the data and a specified method under repeated sampling assumptions. No confidence interval for the primary endpoint is reported in the registry record. Without the endpoint estimate, its variability, and an uncertainty interval, readers cannot assess how precisely the mean concentration was estimated.

What does the analysis population mean?

The record defines the Part A pharmacokinetic set as participants who received at least 1 dose of LUM/IVA in Part A. This is a treatment-exposed population definition. In general, an analysis population should be interpreted according to the endpoint and the rules used to determine eligibility for analysis. The record does not report the number of participants with an available Day 15 measurement, how missing measurements were handled, or whether additional pharmacokinetic eligibility rules were applied. Those details are not reported in the registry record.

What can be inferred from the study structure?

The trial is described as open-label and single-group, with allocation not applicable. In general, open-label means that masking was absent, and a single-group design does not create a randomized concurrent control group. Such a design can describe measurements observed during study participation, but it does not by itself separate a treatment-associated change from other influences, including time, participant characteristics, or the course of the condition. The record’s dose groups are not a like-for-like randomized comparison.

Part A and Part B also have different stated roles. Part A’s primary endpoint concerns pharmacokinetics at Day 15. Part B’s listed outcomes include measurements at Week 24. These endpoints occur at different times and answer different kinds of questions. A pharmacokinetic concentration should not be interpreted as if it were a Week 24 clinical outcome. The registry does not provide numerical results for the listed Week 24 measures.

How should planning calculations be interpreted?

The planning description states that sample-size illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect specified as a fraction of the observed effect. It also states that these are planning illustrations computed from an observed effect, not the trial’s own design. The specific illustration results are not reported in the registry record. Such planning figures, when available, are not observed power and do not change the actual study design. In general, a planning calculation asks how much information a hypothetical future study might need under its stated assumptions; it does not show that the present study had a particular probability of detecting an effect.

Normal approximations are general mathematical tools that can be useful for planning when their assumptions are reasonable. Their suitability depends on the outcome, the design, and the amount and distribution of data. The registry does not report a statistical analysis plan or enough information to assess whether those planning assumptions fit a particular endpoint. It also does not report adjusted analyses, model specifications, or inferential test results for the primary endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcome measures, including the primary Day 15 pharmacokinetic endpoint, adverse events, and Part B measurements at Week 24. When a study assesses several outcomes or several comparisons, the chance of at least one apparently unusual result can increase if each is tested separately. In general, multiplicity procedures can manage that issue by adjusting testing or by defining a hierarchy of outcomes. The registry record does not report a multiplicity strategy, a hierarchy for secondary outcomes, or the statistical analysis plan, so it is not possible to determine how multiple outcomes were handled.

Missing-data handling is also not reported in the registry record. The record defines the Part A pharmacokinetic set by receipt of at least 1 dose, but does not state how participants without a Day 15 concentration were treated, whether measurements were repeated, or whether any imputation method was used. For the Week 24 outcomes, the record does not describe the number with measurements, reasons for missing visits, or methods for addressing missing values.

These omissions matter because analyses can depend on which participants have observed data and on assumptions about why measurements are missing. In general, analyzing only available measurements may give a different result from an analysis that uses all eligible participants under a stated missing-data model. No such method or sensitivity analysis is reported in the registry record.

The record lists no analysis entries. It also does not report confidence intervals or test results for the primary outcome. As a result, multiplicity, missing-data assumptions, and the inferential approach cannot be evaluated for that endpoint from 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: constipation (5.3%), gastroenteritis viral (5.3%), infective pulmonary exacerbation of cystic fibrosis (4.9%).

The registry lists serious adverse-event counts by study part and dose group. For Part A, the LUM 100 mg/IVA 125 mg group lists 0 of 4 participants with a serious adverse event, and the LUM 150 mg/IVA 188 mg group lists 0 of 8. For Part B, the LUM 100 mg/IVA 125 mg group lists 2 of 19, and the LUM 150 mg/IVA 188 mg group lists 2 of 41. The registry lists zero deaths in each of these groups.

It also lists other adverse-event counts: 4 of 4 in the Part A LUM 100 mg/IVA 125 mg group, 6 of 8 in the Part A LUM 150 mg/IVA 188 mg group, 19 of 19 in the Part B LUM 100 mg/IVA 125 mg group, and 40 of 41 in the Part B LUM 150 mg/IVA 188 mg group. These are group-specific counts, not a randomized comparison. The record does not provide further information on event timing, duration, severity, or attribution in these entries.

The registry lists Constipation (5.3%), Gastroenteritis viral (5.3%), and Infective pulmonary exacerbation of cystic fibrosis (4.9%) among the serious adverse-event terms. The denominator and additional context for these percentages are not reported in the registry record. In general, a serious adverse event is classified by regulatory seriousness criteria; seriousness is distinct from the intensity or severity of an event. Counts alone do not establish causation.

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

The study is a record of open-label evaluation of lumacaftor/ivacaftor in young children with cystic fibrosis who were homozygous for F508del. Its primary question was pharmacokinetic: the mean pre-dose concentrations of lumacaftor and ivacaftor on Day 15 in Part A. The registry record does not report the numerical primary endpoint results. Therefore, it does not permit a reader to describe the observed mean concentration, its variability, or its precision.

The adverse-event entries provide counts for serious and other adverse events in the listed groups, and the record lists zero deaths in those groups. These counts are descriptive. Because the study was not randomized and had no concurrent control group, they do not establish how the recorded events compare with what would have occurred under another treatment or without treatment. Nor do the entries alone establish that an event was caused by LUM/IVA.

The record lists secondary outcomes for sweat chloride, body mass index, weight, and stature at Week 24, but does not report numerical results for those measures. It is therefore not possible to characterize their observed changes or uncertainty from this record. Outcome names should not be mistaken for outcome findings.

In general, pharmacokinetic, safety, and clinical outcome measures answer different questions. Drug concentration describes exposure at a specified time; an adverse-event count describes recorded events; and a clinical measurement describes a health-related characteristic. Evidence on one type of measure cannot substitute for missing results on another.

The record also does not report a statistical analysis plan, missing-data methods, or multiplicity approach. These limitations constrain assessment of how estimates were produced and how uncertainty across outcomes was handled. The study record can be used to identify its population, design, endpoints, and listed safety counts, but it does not support a conclusion about comparative treatment effects or the clinical impact of the intervention.

13. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between describing drug exposure and estimating a comparative treatment effect. Its primary endpoint was a Day 15 pharmacokinetic concentration, summarized as a mean and standard deviation in the Part A pharmacokinetic set. That endpoint can characterize a concentration measurement in the treated group, but the registry record does not report its numerical estimate or variability.

The study’s open-label, single-group structure is important when interpreting any observed data. Without randomized allocation to a concurrent control, group contrasts cannot be treated as controlled estimates of treatment effect. The Part A and Part B dose groups also differ by study part, and the record does not establish that they provide a like-for-like comparison. Design structure should therefore guide interpretation before attention is given to any apparent difference across groups.

The listed outcomes span several domains: pharmacokinetics, adverse events, sweat chloride, and growth-related measures. These measures are not interchangeable. A concentration measure describes exposure; safety counts summarize reported events; and the Week 24 measures concern other characteristics. The registry identifies these outcomes but does not report numerical results for the primary endpoint or the listed Week 24 measurements.

Finally, the record illustrates why estimates and uncertainty need to be considered together. A mean without its variability or confidence interval gives limited information about precision, while counts without contextual denominators or a comparison group do not establish relative risk or causality. The registry’s detailed endpoint definitions are useful for understanding what was intended to be measured, but missing results and analysis details limit statistical interpretation.

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 interpreting the primary outcome is that the registry record does not report its numerical results. The endpoint is defined as Day 15 pre-dose concentrations of lumacaftor and ivacaftor, with a mean and standard deviation, but neither the estimates nor uncertainty measures are reported. The number of participants contributing endpoint measurements is also not reported.

The study was open-label, single-group, and had allocation recorded as not applicable. It therefore lacks a randomized concurrent control for estimating comparative effects. The different dose groups and parts should not be treated as interchangeable arms. The record does not report baseline characteristics by group or sufficient detail to evaluate possible differences between them.

The registry lists secondary outcomes, including Week 24 sweat chloride and growth-related measurements, but does not report their numerical results. It also does not report a statistical analysis plan, handling of missing data, multiplicity procedures, or details of any inferential models. These omissions prevent assessment of the analysis choices and the precision of outcome estimates.

The safety entries provide group-level counts and list several serious adverse-event terms, but do not report full context for event timing, duration, severity, or attribution. The denominator and context for the percentages attached to the serious-event terms are not reported in the registry record. No randomized comparison is available to contextualize these counts as relative risks.

The dosing description in the registry record is incomplete. It identifies Part A weight-based groups and some dose information, but the complete regimen is not reported in the registry record. These limitations mean that the study’s design and recorded safety counts can be described, while treatment-effect estimates and several aspects of analysis remain unassessable from the record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Pharmacokinetic Study of Lumacaftor/Ivacaftor in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del — NCT02797132.
• Registry record last updated 2018-10-30; status last verified 2018-09.
• Results first posted 2018-10-30.
• 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 a completed Phase 3, two-part, open-label, multicenter, single-group study of lumacaftor/ivacaftor in children aged 2 through 5 years with cystic fibrosis who were homozygous for F508del. Enrollment was 62. The study started in 2016-05, and primary completion was in 2017-09.

The primary endpoint was mean pre-dose concentration of lumacaftor and ivacaftor at Day 15 in the Part A pharmacokinetic set. Numerical primary endpoint results are not reported in the registry record. Listed secondary outcomes include adverse events and Part B measurements at Week 24. The record includes group-specific adverse-event counts and lists zero deaths in the reported groups, but the nonrandomized design does not support a controlled comparison. Analysis details, including missing-data and multiplicity methods, are not reported in the registry record.