This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study to Evaluate the Safety of Long-term Ivacaftor Treatment in Participants With Cystic Fibrosis Who Are Less Than 24 Months of Age at Treatment Initiation and Have an Approved Ivacaftor-Responsive Mutation (NCT03277196), a non-randomized phase 3 study. The primary outcome is Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03277196 |
| Phase | Phase 3 |
| Condition | Cystic Fibrosis |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 86 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Vertex Pharmaceuticals Incorporated |
| Results posted | Yes |
2. Clinical Question
Population
Participants with cystic fibrosis who were less than 24 months of age when treatment began and had an approved ivacaftor-responsive mutation. The registry record describes a Safety Set comprising participants who received at least 1 dose of study drug.
Intervention
Long-term ivacaftor treatment in an open-label arm. The record describes doses for some age and weight ranges, but the dose description is incomplete, so it does not establish the full dosing schedule for every participant.
Comparator
An observational arm is named in the study summary. Allocation was non-randomized, and the registry record warns that the arms are not a like-for-like control comparison. Details of the observational arm are not reported in the registry record.
Primary question
How many participants experienced treatment-emergent adverse events (TEAEs) and serious TEAEs from Day 1 up to Week 120? This is a safety and tolerability question. The primary outcome is a participant count, not a comparison of treatment effects between randomized groups.
The study concerns long-term treatment in a young population defined by age at treatment initiation and an approved responsive mutation. Its primary outcome focuses on adverse events during follow-up. The registry record also lists absolute change in sweat chloride as a secondary outcome, but does not provide an analysis result for that outcome. The record therefore supports a description of the safety counts posted for the ivacaftor arm, but not a complete assessment of all intended clinical questions.
Because participants were not randomly allocated, the observational arm cannot be treated as an equivalent control group for causal inference. Differences between arms could reflect how participants entered or were managed in each arm, as well as treatment. The posted safety counts are consequently best read as descriptive information about participants in the ivacaftor arm, rather than proof of what would have happened to the same participants without ivacaftor.
3. Trial Design
This was a Phase 3, multicenter, parallel, two-arm study. It was open-label and non-randomized: participants and study staff were not masked, and allocation did not use random assignment. One arm received ivacaftor; the other was observational. The registry record explicitly cautions that these arms are not a like-for-like control comparison. That distinction matters when interpreting any apparent difference between them.
The record gives enrollment as 86 and lists the study status as completed. The study began on 2017-08-16, with primary completion on 2023-10-02. These dates describe the registry record; they do not establish that every participant had the same duration of follow-up. The primary outcome timeframe is Day 1 up to Week 120.
Participants were eligible for the study population described in the summary if they had cystic fibrosis, were less than 24 months of age at treatment initiation, and had an approved ivacaftor-responsive mutation. The ivacaftor arm description states that participants less than 24 months old and weighing 5 to less than 7 kg received 25 mg every 12 hours; those weighing 7 to less than 14 kg received 50 mg every 12 hours; and those weighing 14 to less than 25 kg received 75 mg every 12 hours. The remaining dose description is incomplete in the registry record, so the full regimen should not be inferred from this excerpt.
The study summary describes the purpose as evaluating safety and efficacy, while the stated primary outcome is safety and tolerability. The secondary outcome listed is absolute change in sweat chloride. Detailed criteria for entry into the observational arm, treatment assignment procedures, follow-up schedules beyond the primary timeframe, and the protocol’s statistical plan are not reported in the registry record. In particular, the non-randomized design and lack of masking should be kept in mind when judging the scope of the evidence.
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: Rollover participants (who completed parent study VX15-770-124 \[NCT02725567\] Part B or Part A/B) and IVA-naïve participants (who participated in study VX15-770-124 Part A only or who did not participate in VX15-770-124 and were less than (\<) 24 months of age at the Day 1 of current study \[VX15-770-126\]) were enrolled in this study.
Overall Study
| Stage | Ivacaftor Treatment |
|---|---|
| STARTED | 86 |
| Rollover Participants | 38 |
| IVA-Naïve Participants | 48 |
| COMPLETED | 58 |
| NOT COMPLETED | 28 |
Reasons for not completing this period:
| Reason | Ivacaftor Treatment |
|---|---|
| Commercial Drug is Available for Participants | 20 |
| Lost to Follow-up | 3 |
| Withdrawal of Consent (not due to AE) | 3 |
| Other | 2 |
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 in this study.
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 was analyzed on safety Set which is defined as all participants who received at least 1 dose of study drug.
| Characteristic | Unit | Ivacaftor Treatment |
|---|---|---|
| Participants analysed | 86 | |
| Age, Continuous | months | 10.2 (SD 5.19) |
| Sex: Female, Male: Female | Participants | 40 |
| Sex: Female, Male: Male | Participants | 46 |
| Race/Ethnicity, Customized: Hispanic or Latino | Participants | 2 |
| Race/Ethnicity, Customized: Not Hispanic or Latino | Participants | 79 |
| Race/Ethnicity, Customized: Not collected per local regulations | Participants | 5 |
| Race/Ethnicity, Customized: White | Participants | 82 |
| Race/Ethnicity, Customized: Asian | Participants | 1 |
| Race/Ethnicity, Customized: Not collected per local regulations | Participants | 3 |
6. Primary Endpoint
The registry lists the primary outcome as Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs, measured over Day 1 up to Week 120.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary outcome counts participants with treatment-emergent adverse events (TEAEs) and serious TEAEs during the period from Day 1 up to Week 120. The unit is participants, and the Safety Set includes participants who received at least 1 dose of study drug in this study. The outcome therefore describes the number of people with events, rather than the total number of event episodes.
Safety outcomes are used to characterize adverse events observed while participants receive treatment and to identify events classified as serious. Reporting both TEAEs and serious TEAEs provides different levels of safety description: the broad count captures participants with treatment-emergent events, while the serious-event count focuses on events designated serious. The registry record does not give the criteria used to classify seriousness, so that classification cannot be independently interpreted from the record alone.
Counts are useful for showing how many participants in the Safety Set were affected, but they do not by themselves describe event timing, duration, recurrence, severity beyond the serious classification, or whether an event was judged related to treatment. Nor do counts alone establish a causal effect. Interpreting them requires attention to the study’s open-label, non-randomized design and to the period over which events were collected. The registry record does not report a comparative statistical analysis of these outcomes.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
In the ivacaftor arm, the posted results report 21 participants with serious adverse events among 86 at risk, and 83 participants with other adverse events among 86 at risk. The record reports 0 deaths. These are descriptive counts from the arm, not estimates from a randomized comparison. The counts indicate that adverse events were reported for many participants during the stated safety observation period, while the serious-event count describes a narrower category.
The most frequently listed serious adverse-event term is infective pulmonary exacerbation of cystic fibrosis, reported as 10.5%. Other listed terms are constipation and Pseudomonas test positive, each reported as 2.3%, and adrenocortical insufficiency acute, distal intestinal obstruction syndrome, and pyrexia, each reported as 1.2%. These percentages are quoted as recorded. They describe reported terms and do not establish that ivacaftor caused them. The registry record does not provide a treatment-relatedness assessment alongside these figures.
The counts should not be interpreted as a comparison of risks between treatment and observation. The study used non-randomized allocation, and the registry record specifically says the arms are not a like-for-like control comparison. Without random assignment, differences in participant characteristics, clinical circumstances, or other factors may contribute to differences between arms. The posted data do not remove those potential sources of confounding.
Counts also do not express precision in the way an interval estimate would. A confidence interval would communicate uncertainty around an estimated quantity, but a confidence interval for these safety outcomes is not reported in the registry record. No p-value, adjusted estimate, or inferential comparison for the primary outcome is listed. Accordingly, the figures support a descriptive reading of what was recorded in the ivacaftor arm, not a formal claim that one arm had a higher or lower event risk.
The primary outcome timeframe extends from Day 1 up to Week 120, but a shared maximum timeframe does not mean that all participants contributed equal time at risk. Individual follow-up and exposure details are not reported in the registry record. This matters because simple participant counts do not account for differences in time observed or treatment exposure. The record also does not provide details on event onset, recurrence, discontinuation, or missing safety assessments.
Overall, the posted results describe substantial event reporting in the treated arm and identify the serious-event terms recorded most often. They do not, on their own, establish causation, quantify comparative treatment effects, or resolve the safety profile beyond the outcomes and classifications entered in the registry record.
9. Statistical Methods Explained
The central statistical feature of the primary outcome is that it is a count of participants with an event. The registry record gives separate counts for serious adverse events and other adverse events in the ivacaftor arm. Such counts answer a descriptive question: how many participants in the defined Safety Set were recorded as having an event during the stated timeframe? They are not counts of every episode, and they are not automatically comparable with counts from a group assembled in a different way.
What does a participant count convey?
A participant count treats each participant as the unit of analysis for the outcome. If one participant has more than one event, a count of participants with an event does not convey how many episodes occurred. A participant count also does not show when an event occurred, how long it lasted, or whether the same participant experienced multiple event types. Those details require event-level information, which is not reported in the registry record.
In general, a rate can account for differing observation time by relating event occurrence to time at risk. That is a different quantity from a simple participant count. The registry record supplies an at-risk count for the ivacaftor arm but does not report person-time or individual follow-up duration. It is therefore not possible to use the posted counts to describe a person-time rate from the registry record.
Why does study design affect interpretation?
Random allocation is intended to balance, on average, factors that could affect outcomes across groups. This study was non-randomized, so that design-based protection is absent. The study also was open-label, meaning treatment assignment was not masked. In general, lack of masking may influence event reporting, assessment, or decisions about whether an event meets a category, depending on the outcome and procedures. The registry record does not report procedures that would allow the extent of any such influence to be assessed.
The observational arm is not a randomized control arm. Even a numerical contrast between arms would not isolate the effect of treatment without additional assumptions and analysis. The registry record cautions against treating the groups as like-for-like controls. No adjusted comparison or model is reported, so interpretation should remain focused on the descriptive result for the ivacaftor arm.
What would an uncertainty interval add?
In general, a confidence interval gives a range of values compatible with the observed data under a specified statistical method and its assumptions. It helps distinguish a relatively precise estimate from one with substantial uncertainty. A confidence interval does not by itself remove bias, correct a non-randomized comparison, or show that an observed association is causal. The registry record does not report confidence intervals for the primary safety counts, so their statistical precision cannot be evaluated from the posted results alone.
Likewise, a p-value is a measure calculated under a statistical model and a null hypothesis; it is not the probability that a treatment works or that a result is due to chance. No p-value or formal primary-outcome analysis is listed in the registry record. It would be inappropriate to infer a hypothesis test or a prespecified analysis that is not recorded.
How should planning illustrations be read?
Planning illustrations based on an observed effect are not results from a prospective power calculation for this study, and they are not observed power. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is expressed as a fraction of the observed effect. For non-time-to-event outcomes, the planning quantity is participants per arm; for time-to-event outcomes, it is the total number of events. These assumptions describe an illustration, not the trial’s own design justification. The sponsor’s sample-size justification and any protocol-specific calculation are not reported in the registry record.
General caution applies when planning from an observed effect: the observed effect may be uncertain, and an illustration based on it does not guarantee the same result in a future study. It should not be interpreted as evidence that the trial had a particular probability of detecting an effect. No numerical planning estimates or sponsor power calculation are reported in the registry record.
What can be concluded from the registry analysis entries?
The registry record lists no analysis entries. It therefore does not document the model, covariate adjustment, handling of repeated events, or inferential approach used for the outcomes. No statistical method beyond the description of the outcome as a participant count should be attributed to the sponsor on the basis of this record. Any broader statistical interpretation should separate general methodological principles from the analyses actually documented.
Over-dispersion is a general issue for count data when variability exceeds what a chosen count model expects. It matters when modeling event counts, especially if event numbers vary substantially across participants. The primary outcome is described as participants with events, rather than an episode count, and the registry record does not report a count model. Over-dispersion therefore cannot be evaluated from the posted participant counts alone.
10. Multiplicity, Missing Data and Analysis Populations
The registry record identifies safety and tolerability as the primary outcome and lists absolute change in sweat chloride as a secondary outcome. It does not describe a multiplicity strategy, such as an adjustment for testing several outcomes or time points. A multiplicity approach is not reported in the registry record. Without that information, the handling of any family of statistical tests cannot be assessed. The record lists no analysis entries, so it also does not show which outcomes were included in formal testing or how any tests were ordered.
Missing-data methods are not reported in the registry record. The record does not explain how participants with incomplete follow-up, missing assessments, or discontinued treatment were handled in the outcome calculations. The safety outcome uses the Safety Set, defined as participants who received at least 1 dose of study drug. That definition identifies who is included in the stated population, but does not by itself explain how missing event information within that population was handled.
The registry record does not report an intention-to-treat analysis population or a separate population for the observational arm’s outcomes. It gives safety counts for the ivacaftor arm and an at-risk count for that arm. Because allocation was non-randomized and the groups are not described as like-for-like controls, the posted record does not support treating any cross-arm contrast as a conventional randomized analysis.
These omissions limit reproducibility and the assessment of potential bias. They do not show that missing data or multiplicity were mishandled; they mean that the relevant procedures are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Ivacaftor Arm | 21 | 86 | 24.4% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Ivacaftor Arm | 0 of 86 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Ivacaftor Arm | 83 of 86 |
Most frequent serious adverse event terms
| Event term | Organ system | Ivacaftor Arm |
|---|---|---|
| Infective pulmonary exacerbation of cystic fibrosis | Infections and infestations | 9 of 86 |
| Constipation | Gastrointestinal disorders | 2 of 86 |
| Pseudomonas test positive | Investigations | 2 of 86 |
| Adrenocortical insufficiency acute | Endocrine disorders | 1 of 86 |
| Distal intestinal obstruction syndrome | Gastrointestinal disorders | 1 of 86 |
| Pyrexia | General disorders | 1 of 86 |
| Bronchiolitis | Infections and infestations | 1 of 86 |
| Bronchitis | Infections and infestations | 1 of 86 |
| Gastroenteritis | Infections and infestations | 1 of 86 |
| Gastroenteritis viral | Infections and infestations | 1 of 86 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Ivacaftor Arm |
|---|---|---|
| Cough | Respiratory, thoracic and mediastinal disorders | 60 of 86 |
| Pyrexia | General disorders | 34 of 86 |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | 33 of 86 |
| Upper respiratory tract infection | Infections and infestations | 24 of 86 |
| Vomiting | Gastrointestinal disorders | 22 of 86 |
| Rash | Skin and subcutaneous tissue disorders | 21 of 86 |
| Ear infection | Infections and infestations | 19 of 86 |
| Diarrhoea | Gastrointestinal disorders | 15 of 86 |
| Constipation | Gastrointestinal disorders | 13 of 86 |
| Infective pulmonary exacerbation of cystic fibrosis | Infections and infestations | 13 of 86 |
Serious events with the highest arm-level rate: infective pulmonary exacerbation of cystic fibrosis (10.5%), constipation (2.3%), pseudomonas test positive (2.3%), adrenocortical insufficiency acute (1.2%), distal intestinal obstruction syndrome (1.2%).
The safety results report 21 participants with serious adverse events among 86 at risk in the ivacaftor arm. The count for other adverse events is 83 among 86 at risk, and the record reports 0 deaths. These values are participant counts, not totals of every event episode. The serious-event terms listed include infective pulmonary exacerbation of cystic fibrosis at 10.5%; constipation and Pseudomonas test positive at 2.3% each; and adrenocortical insufficiency acute, distal intestinal obstruction syndrome, and pyrexia at 1.2% each.
Those term percentages should be read as the percentages reported for the listed serious-event terms. The registry record does not clarify the relationship between participants and repeated occurrences of a term, or provide the event-level detail needed to reconstruct the percentages independently. The record also does not state, alongside these results, whether each event was considered related to treatment.
Seriousness is a classification, not a statement about cause. The registry record does not give the seriousness criteria or provide a randomized comparison. These results therefore describe what was recorded in the ivacaftor arm; they do not establish that treatment caused an event or that its frequency differs from what would have occurred without treatment.
12. What the Result Does, and Does Not, Mean
The results establish what the registry record reports for the primary safety outcome in the ivacaftor arm: participant counts for serious and other adverse events during the period from Day 1 up to Week 120. They also identify several serious-event terms and report 0 deaths. This is useful descriptive information about the safety observations entered for the study population.
The results do not establish that ivacaftor caused any particular event. A treatment-emergent event is recorded in a treatment context, but timing alone does not demonstrate causality. The registry record does not provide treatment-relatedness assessments for the listed serious events. The reported counts also do not establish how event risk compares with a population receiving no treatment or another treatment.
The non-randomized design is central to the limits of interpretation. The observational arm is not a like-for-like control comparison according to the registry record. Participants in the arms may differ for reasons related to assignment or care, and the record does not report an adjusted analysis designed to address such differences. A descriptive comparison cannot be treated as a randomized estimate of a treatment effect.
The record also does not provide confidence intervals, p-values, or a documented statistical analysis for the primary safety outcome. The counts therefore cannot be used to judge the precision of an estimated treatment effect, and no formal statistical significance claim is supported. Counts alone also do not describe individual follow-up time, event duration, severity beyond the serious classification, or recurrence.
The study summary refers to both safety and efficacy, and the registry record lists absolute change in sweat chloride as a secondary outcome. However, an analysis result for that outcome is not reported in the registry record. The posted safety data should not be taken as a complete account of all study outcomes or as a complete evaluation of efficacy. The most defensible interpretation is limited to the documented safety counts, their stated population and timeframe, and the design constraints attached to them.
13. Why This Trial Matters Statistically
This study is statistically notable because it focuses on a young, mutation-defined cystic fibrosis population and records safety outcomes during long-term ivacaftor treatment. Describing the population and the observation period is important when reading safety data: counts are meaningful only in relation to who was observed and the period during which events could be recorded. The registry record defines the Safety Set and gives the primary timeframe as Day 1 up to Week 120.
The design also illustrates why an observational arm should not automatically be treated as a control group. Randomization supports a particular kind of group comparison; this study did not use random allocation. The record itself cautions that the arms are not a like-for-like control comparison. Recognizing that limitation prevents a descriptive contrast from being mistaken for a causal estimate.
Safety reporting is most informative when the unit and classification are clear. Here, the primary outcome is expressed as participants with TEAEs and serious TEAEs, while listed serious-event terms are reported with percentages. These measures describe different aspects of the record and do not disclose every event-level detail. The distinction between participant counts and event episodes is important for avoiding over-interpretation.
The registry record also demonstrates the value of transparent statistical documentation. Information about analysis methods, missing-data handling, multiplicity, and precision estimates is not reported. Their absence in the record constrains independent assessment; it does not prove that the sponsor did not conduct such work. Clear reporting would allow readers to understand how the observed safety data were analyzed and what uncertainty surrounds any estimate.
Finally, a planning illustration based on an observed effect is not a substitute for a trial’s prospective design rationale. Keeping planning assumptions separate from observed results helps prevent sample-size calculations from being misread as evidence of study power or treatment effect.
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 interpretation is the non-randomized design. Participants were not randomly allocated, and the registry record explicitly cautions that the arms are not a like-for-like control comparison. Any comparison between the ivacaftor and observational arms would therefore be vulnerable to differences between participants and other potential confounding. No adjusted comparative analysis is reported.
The study was open-label, so treatment assignment was not masked. The registry record does not describe blinded outcome assessment or other procedures intended to limit the influence of knowledge of treatment assignment on reporting and classification. The primary outcome concerns adverse events, for which recording and assessment procedures can be relevant.
The available arm description is incomplete. It gives some ivacaftor doses by age and weight, but cuts off before the full description is provided. The observational arm description is blank in the registry record. As a result, the complete treatment regimen and the details of the observational condition cannot be reconstructed from this record.
Statistical reporting is also limited. No analysis entries, confidence intervals, p-values, or documented model are listed. Methods for missing data, multiplicity, participant follow-up, and event-level handling are not reported in the registry record. Although the Safety Set is defined as participants who received at least 1 dose, that definition does not answer how incomplete observations were handled.
The primary timeframe extends to Week 120, but individual exposure and follow-up duration are not reported. Participant counts cannot account for differences in time at risk. The registry record also does not state whether serious events were judged related to treatment, nor does it provide the criteria used to classify seriousness. These limitations narrow the conclusions to a descriptive account of the posted safety data.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study to Evaluate the Safety of Long-term Ivacaftor Treatment in Participants With Cystic Fibrosis Who Are Less Than 24 Months of Age at Treatment Initiation and Have an Approved Ivacaftor-Responsive Mutation — NCT03277196.
- Registry record last updated 2024-10-23; status last verified 2024-10.
- Results first posted 2024-10-23.
- 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.
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18. Record Summary
The registry record describes a completed Phase 3, multicenter, parallel, two-arm study of long-term ivacaftor in participants with cystic fibrosis who were less than 24 months of age at treatment initiation and had an approved ivacaftor-responsive mutation. The study was open-label and non-randomized, with an ivacaftor arm and an observational arm. The record cautions that the arms are not a like-for-like control comparison.
The primary outcome is the number of participants with TEAEs and serious TEAEs from Day 1 up to Week 120. In the ivacaftor arm, the record reports 21 participants with serious adverse events among 86 at risk, 83 with other adverse events among 86 at risk, and 0 deaths. Absolute change in sweat chloride is listed as a secondary outcome, but its analysis result is not reported in the registry record.
Detailed statistical methods, missing-data procedures, multiplicity handling, and uncertainty estimates are not reported in the registry record. The posted results are therefore best interpreted as descriptive safety information, with causal and comparative conclusions limited by the study design and available analysis details.