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 Study of Ataluren in Nonsense Mutation Cystic Fibrosis (ACT CF) (NCT02139306), a randomized phase 3 study. The primary outcome is Absolute Change From Baseline in Percent-predicted Forced Expiratory Volume in One Second (ppFEV1) at Week 48.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02139306 |
| Phase | Phase 3 |
| Condition | Cystic Fibrosis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 279 |
| Arms in the primary outcome | 2 |
| Lead sponsor | PTC Therapeutics |
| Results posted | Yes |
2. Clinical Question
Population
The trial enrolled people with nonsense mutation cystic fibrosis who were not receiving chronic inhaled aminoglycosides. The registry reports 279 participants enrolled. The primary analysis population was defined as randomized participants with FEV1 data at baseline and at least one post-baseline visit; the arm counts reported for the primary outcome were 138 for ataluren and 136 for placebo.
Intervention
Participants assigned to ataluren received oral powder for suspension at morning, midday and evening doses of 10, 10 and 20 mg/kg, respectively. Treatment was planned for 48 weeks or until treatment discontinuation.
Comparator
The comparison group received matching placebo orally at morning, midday and evening, for 48 weeks or until treatment discontinuation. The study was randomized and placebo-controlled.
Primary question
The primary question was whether the average change from baseline in percent-predicted FEV1 at Week 48 differed between the ataluren and placebo groups. The registry defines the Week 48 change as the average of the changes from baseline at Week 40 and Week 48. The posted between-group estimate was 0.597 percentage points, with a 95% confidence interval that included zero and a reported p-value of 0.534.
3. Trial Design
This was a Phase 3, randomized, parallel-group, placebo-controlled study of ataluren in nonsense mutation cystic fibrosis. The registry lists the study as quadruple-masked, while its brief description calls it double-blind. It was international and multicenter. The registry reports 279 participants enrolled and the study status as completed.
Participants received ataluren or matching placebo orally at morning, midday and evening. The ataluren regimen was 10, 10 and 20 mg/kg at those respective times. Both groups were assigned treatment for 48 weeks or until treatment discontinuation. The study focused on participants not receiving chronic inhaled aminoglycosides, as stated in the registry's brief description.
The primary outcome was assessed in an intent-to-treat population defined in the registry as randomized participants with baseline FEV1 data and at least one post-baseline visit. The reported primary-outcome arm counts were 138 for ataluren and 136 for placebo. The adverse-event groups were reported separately, with 140 participants at risk in the ataluren group and 139 in the placebo group. These outcome-specific denominators should not be treated as interchangeable.
The registry lists pulmonary exacerbations, respiratory quality of life, body mass index, and several adverse-event measures among the secondary outcomes. The record does not report the rationale for the enrollment target or the trial's sample-size justification. It also does not report enough information to establish whether every randomized participant completed treatment or contributed data to each outcome.
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.
Overall Study
| Stage | Ataluren | Placebo |
|---|---|---|
| STARTED | 140 | 139 |
| COMPLETED | 127 | 125 |
| NOT COMPLETED | 13 | 14 |
Reasons for not completing this period:
| Reason | Ataluren | Placebo |
|---|---|---|
| Withdrawal by Subject | 4 | 6 |
| Adverse Event | 3 | 4 |
| Physician Decision | 0 | 1 |
| Other Unspecified | 2 | 3 |
| Protocol Violation | 4 | 0 |
Analysis population for the primary outcome, as defined in the registry: The intent-to-treat (ITT) population included all randomized participants who had FEV1 data available at Baseline and at least one post-baseline visit.
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 as-treated population included all randomized participants who actually received any study treatment.
| Characteristic | Unit | Ataluren | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 140 | 139 | 279 | |
| Age, Continuous | years | 22.0 (SD 11.0) | 22.0 (SD 10.44) | 22.0 (SD 10.70) |
| Sex: Female, Male: Female | Participants | 59 | 74 | 133 |
| Sex: Female, Male: Male | Participants | 81 | 65 | 146 |
6. Primary Endpoint
The registry lists the primary outcome as Absolute Change From Baseline in Percent-predicted Forced Expiratory Volume in One Second (ppFEV1) at Week 48, measured over From Baseline to Week 48.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | Percentage of predicted FEV1 |
| Endpoint classification | Continuous Endpoint |
The primary endpoint was absolute change from baseline in percent-predicted forced expiratory volume in one second (ppFEV1) at Week 48. FEV1 is the volume of air forcibly exhaled in one second, measured by spirometry. Expressing FEV1 as a percentage of a predicted value places the observed volume in relation to a reference expectation, rather than reporting only a raw volume.
The registry defines the Week 48 endpoint as the average of the change from baseline at Week 40 and the change from baseline at Week 48. Baseline ppFEV1 was itself defined as the average of measurements at screening and the baseline visit. This definition uses measurements at more than one visit in forming the endpoint, rather than relying on a single Week 48 change.
FEV1 is used as a measure of lung function. For a randomized comparison, the central statistical question is whether the average change differs between the assigned groups, and how precisely that difference is estimated. The posted ataluren mean was -1.396 percentage points and the placebo mean was -1.992 percentage points. The reported net mean difference was 0.597 percentage points. That estimate is not, by itself, evidence of a clear group difference: its 95% confidence interval included zero, and the reported p-value was 0.534.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary results show declines in mean ppFEV1 from baseline in both groups: -1.396 percentage points for ataluren and -1.992 percentage points for placebo. The reported net mean difference was 0.597 percentage points in favor of the ataluren group’s mean change. However, the estimated difference is small relative to the uncertainty represented by its 95% confidence interval, which extended across zero. The reported p-value was 0.534.
A confidence interval that includes zero is compatible with no average difference between groups as well as with differences in either direction within the interval. It therefore does not establish that the groups had identical outcomes. The p-value likewise does not measure the probability that ataluren is effective or ineffective. It describes how compatible the observed data are with the statistical null hypothesis under the analysis used. The registry result does not provide a precise estimate that resolves the direction or size of a possible difference.
The arm-specific 95% confidence intervals also show uncertainty around each group’s mean change. Those intervals are not a substitute for the interval around the between-group contrast: the trial’s comparative question is addressed by the reported net mean difference and its confidence interval. The posted comparison uses a mixed-model, repeated-measures analysis. The arm means alone do not reproduce all features of that model.
The primary result should be read as an estimate with substantial uncertainty, not as proof of no difference. Nor does a numerical point estimate in favor of ataluren establish a treatment effect. The result describes the particular endpoint, population, time frame and analysis recorded for this trial.
Secondary outcomes add context but do not overturn or independently settle the primary result. The registry reports a negative binomial regression for the pulmonary-exacerbation rate, with a confidence interval for the rate ratio that includes the no-difference value. Other posted secondary comparisons are based on sparse or modest event counts and do not carry the same role as the stated primary endpoint. Their unadjusted analyses are also subject to the increased chance of chance findings when multiple outcomes are examined.
The results are limited to the enrolled population and the study conditions described in the registry. They do not establish what would occur in people outside the stated population, or under treatment circumstances not represented in this trial. They also do not provide a basis for individual treatment decisions.
9. Statistical Methods Explained
The primary endpoint is continuous: each participant contributes a measure of change in ppFEV1, and the analysis compares group means. The registry reports a least-squares mean for each arm and a net mean difference from a mixed-model, repeated-measures analysis. A least-squares mean is a model-based group estimate; it is not necessarily identical to a simple arithmetic average of all observed values. The registry does not report the full model specification, covariates, covariance structure, or detailed missing-data assumptions.
What does the confidence interval convey?
In general, a confidence interval describes the range of values reasonably compatible with the data and the statistical model at the stated confidence level. The reported primary 95% interval for the between-group mean difference includes zero. Zero is the value corresponding to no difference in mean change between groups. Thus, the interval indicates that the posted data do not pin down the comparative effect precisely enough to rule out no difference. An interval is not a guarantee that the true value lies inside it, nor does it assign a probability to each possible effect.
What does the mixed-model analysis do?
In general, a repeated-measures model analyzes outcome observations collected across visits while accounting for their within-participant structure. Such models can use repeated observations rather than treating each visit as unrelated. The registry identifies the method but does not give enough detail to determine the exact model terms or how missing observations were handled. It would therefore be inappropriate to infer a particular covariate adjustment, imputation procedure, or missing-at-random assumption.
How should the event-rate comparison be read?
Pulmonary exacerbations are counted events, so the secondary outcome is a rate rather than a continuous mean or a simple participant-level yes/no outcome. The sponsor-reported analysis used negative binomial regression and reported a rate ratio with a 95% confidence interval that includes one, the no-difference value for a ratio. In general, negative binomial models can accommodate over-dispersion, which occurs when count variability exceeds what a simple Poisson model allows. The registry does not report the model diagnostics or detailed specification.
A separate simple re-calculation of the posted summary statistics uses a Poisson assumption. That is a different, unadjusted approach and should not replace the sponsor-reported negative binomial analysis. In general, if event counts are more variable than a Poisson model assumes, the Poisson model can understate uncertainty. The re-calculation is best treated as an illustration of what the summary rates imply under its stated assumptions, not as a replication of the trial analysis.
What do the binary comparisons represent?
For binary outcomes, a risk difference compares the proportion of participants with an event between groups. Zero is the no-difference value for a risk difference. A confidence interval crossing zero does not establish a group difference. The simple comparisons based on the posted counts are unadjusted and may be imprecise, particularly when events are uncommon. The registry does not report sponsor analyses for the posted laboratory-parameter and electrocardiogram comparisons.
How should planning illustrations be understood?
Planning illustrations based on observed effects are not observed power and do not explain how the trial’s enrollment target was selected. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect set to the stated fraction of the observed effect. For pulmonary-exacerbation-rate planning, the posted figures are participants per arm: planning for 100% of the observed effect gives 568 participants per arm for 80% power and 760 for 90% power; planning for 75% gives 986 and 1,319; planning for 50% gives 2,168 and 2,902. These are illustrations of hypothetical planning scenarios, not the number enrolled or evidence about the trial’s actual power. The registry record does not report its own sample-size justification.
What does multiplicity change?
When several outcomes are analyzed, each unadjusted test creates an opportunity for a chance-positive result. In general, multiplicity procedures can limit that risk by adjusting how evidence is assessed across tests. The registry record does not report a multiplicity-adjustment strategy or a hierarchy for the secondary outcomes. The primary endpoint remains the clearest prespecified focus in the record; unadjusted secondary p-values, where available, should be interpreted cautiously rather than as independent confirmation.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| Mixed-model, repeated-measures | Mean Difference (Net) 0.597 | -1.2881 to 2.4813 | 0.534 |
The registry reports the primary comparison as a mixed-model, repeated-measures analysis. Its net mean difference was 0.597 percentage points, with a reported 95% confidence interval extending from -1.288 to 2.481 and p=0.534. The interval includes zero, so the sponsor-reported analysis does not establish a clear difference in mean ppFEV1 change between the groups.
The arm-level means and confidence intervals are descriptive summaries, while the sponsor’s comparison comes from the repeated-measures model. A simple comparison reconstructed from arm summaries would not necessarily match a model that uses repeated visits and its own assumptions. The registry does not report sufficient detail to reproduce the mixed-model analysis independently.
For pulmonary exacerbations, the sponsor-reported method was negative binomial regression, with a rate ratio of 0.857, a 95% confidence interval from 0.597 to 1.229, and p=0.401. The confidence interval includes one, the no-difference value for a rate ratio. The posted simple re-calculation uses a Poisson assumption and unadjusted summary data, so it is not a substitute for the sponsor’s model-based result. In general, the sponsor-reported analysis is the relevant trial analysis; a simple re-calculation is supplementary and answers a narrower question.
The registry does not report sponsor analyses for the posted laboratory-parameter and electrocardiogram comparisons. Those simple comparisons should not be presented as if they were sponsor-reported trial analyses.
11. Multiplicity, Missing Data and Analysis Populations
The registry defines the primary outcome and identifies several secondary outcomes, but it does not report a multiplicity-adjustment plan, a hierarchy of hypotheses, or a gatekeeping procedure. This matters because testing multiple outcomes can increase the chance of obtaining a nominally unusual result even when there is no underlying effect. An unadjusted p-value for a secondary outcome should therefore not be interpreted as though it were the sole planned test. The absence of a reported adjustment does not prove that none was used; it means the registry record does not describe one.
The record also does not report the detailed missing-data strategy for the primary analysis. It defines the intent-to-treat population as randomized participants who had baseline FEV1 data and at least one post-baseline visit. That operational definition excludes randomized participants without those data from the stated analysis population, so it is not equivalent to saying that every randomized participant contributed to the endpoint analysis. The record does not report the number of participants with missing outcome data by reason, the model’s assumptions about missingness, or sensitivity analyses addressing departures from those assumptions.
For the secondary outcomes, the registry does not give a complete account of outcome-specific analysis populations or missingness. The adverse-event summaries use their own risk-group denominators. Those counts should be interpreted for the safety summaries as reported, rather than assumed to match the primary endpoint population. For some listed outcomes, comparative estimates or analyses are not reported in the registry record.
These omissions limit how fully the analyses can be assessed from the registry alone. They do not invalidate the posted estimates, but they leave uncertainty about how missing observations and the family of outcomes were handled. The primary comparison should be read as the reported model-based result, while unadjusted secondary findings warrant particular caution.
12. 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 |
|---|---|---|---|
| Ataluren | 40 | 140 | 28.6% |
| Placebo | 46 | 139 | 33.1% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Ataluren | 0 of 140 |
| Placebo | 0 of 139 |
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 |
|---|---|
| Ataluren | 123 of 140 |
| Placebo | 120 of 139 |
Most frequent serious adverse event terms
| Event term | Organ system | Ataluren | Placebo |
|---|---|---|---|
| Infective pulmonary exacerbation of cystic fibrosis | Infections and infestations | 25 of 140 | 34 of 139 |
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | 4 of 140 | 1 of 139 |
| Pneumonia | Infections and infestations | 1 of 140 | 2 of 139 |
| Nephrolithiasis | Renal and urinary disorders | 3 of 140 | 0 of 139 |
| Pseudomonas infection | Infections and infestations | 2 of 140 | 0 of 139 |
| Bronchopneumonia | Infections and infestations | 1 of 140 | 1 of 139 |
| Sinusitis | Infections and infestations | 0 of 140 | 2 of 139 |
| Nasal polyps | Respiratory, thoracic and mediastinal disorders | 1 of 140 | 1 of 139 |
| Diabetes mellitus | Metabolism and nutrition disorders | 1 of 140 | 1 of 139 |
| Aspergillus infection | Infections and infestations | 1 of 140 | 0 of 139 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Ataluren | Placebo |
|---|---|---|---|
| Infective pulmonary exacerbation of cystic fibrosis | Infections and infestations | 75 of 140 | 78 of 139 |
| Cough | Respiratory, thoracic and mediastinal disorders | 25 of 140 | 25 of 139 |
| Viral upper respiratory tract infection | Infections and infestations | 27 of 140 | 21 of 139 |
| Upper respiratory tract infection | Infections and infestations | 21 of 140 | 21 of 139 |
| Headache | Nervous system disorders | 12 of 140 | 16 of 139 |
| Sinusitis | Infections and infestations | 16 of 140 | 11 of 139 |
| Diarrhoea | Gastrointestinal disorders | 13 of 140 | 12 of 139 |
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | 12 of 140 | 10 of 139 |
| Nausea | Gastrointestinal disorders | 11 of 140 | 10 of 139 |
| Pyrexia | General disorders | 9 of 140 | 10 of 139 |
Serious events with the highest arm-level rate: infective pulmonary exacerbation of cystic fibrosis (24.5%), haemoptysis (2.9%), nephrolithiasis (2.1%), pneumonia (1.4%), sinusitis (1.4%).
The adverse-event record reports serious adverse events in 40 of 140 participants at risk in the ataluren group and 46 of 139 at risk in the placebo group. These are participant counts, not a comparison adjusted for exposure time or differences in follow-up. The record reports zero deaths in each group. The most frequently listed serious term was infective pulmonary exacerbation of cystic fibrosis, reported as 24.5%; other listed serious terms include haemoptysis, nephrolithiasis, pneumonia, sinusitis and Pseudomonas infection.
Serious adverse-event summaries describe events recorded during the study and do not, by themselves, establish that study treatment caused an event. The registry also reports other treatment-emergent adverse events in 123 of 140 participants in the ataluren group and 120 of 139 in the placebo group. A count of participants with at least one event does not convey the number of events per participant, duration, or clinical course. The record’s safety figures should therefore be read as descriptive group summaries, not as proof of a causal safety difference or equivalence.
13. What the Result Does, and Does Not, Mean
The primary result is an estimate of the average difference between ataluren and placebo in change in ppFEV1 over the defined Week 48 endpoint. The estimate was 0.597 percentage points, and the 95% confidence interval included zero. This means the registry’s primary analysis does not clearly distinguish a group difference from no difference. It does not prove that the treatments had identical effects, nor does it establish a benefit from the numerical direction of the estimate.
The result is specific to the trial’s population, treatment schedule, follow-up period and outcome definition. The registry describes people with nonsense mutation cystic fibrosis who were not receiving chronic inhaled aminoglycosides. It does not establish that the same result applies to populations or circumstances not represented in the study.
Secondary outcomes provide additional observations, but their differing endpoints and statistical methods mean they cannot be treated as interchangeable with ppFEV1. The pulmonary-exacerbation result is also imprecise, and some secondary entries lack sponsor-reported comparisons. The absence of a reported multiplicity strategy further limits the strength of conclusions drawn from multiple unadjusted secondary analyses.
These registry results do not answer every question about treatment effects, longer-term outcomes, or safety. They are not a substitute for a complete clinical and statistical assessment, and they do not support individual medical advice. Their most direct statistical message is narrower: the posted primary estimate is uncertain, with its confidence interval encompassing no average difference.
14. Why This Trial Matters Statistically
This trial illustrates why a point estimate should be interpreted together with its confidence interval. The primary net mean difference is positive, but its interval includes zero and spans effects in both directions. Reporting only the point estimate would make the result appear more definite than the posted analysis supports. Reporting only that the result was not statistically significant would also be incomplete, because it would hide the range of effects still compatible with the data.
The study also shows why the model matters. A repeated-measures analysis of a continuous endpoint and a negative binomial analysis of event counts answer different questions and rely on different assumptions. A simple re-calculation from summary statistics can be useful for orientation, but it cannot reproduce an analysis that uses repeated observations or a count model. Apparent differences between methods need to be interpreted in light of what each analysis uses.
Finally, a trial’s secondary endpoints and safety summaries contribute context without necessarily providing confirmatory evidence. Multiple comparisons, incomplete reporting of analysis plans, and outcome-specific denominators all affect how confidently findings can be interpreted. The record supports a careful reading of uncertainty rather than a categorical conclusion.
15. 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.
Important details needed to fully assess the analysis are not reported in the registry record. These include the trial’s sample-size justification, the detailed mixed-model specification, its missing-data assumptions and sensitivity analyses, and a strategy for multiplicity across outcomes. Without those details, the reported primary analysis cannot be independently reconstructed from the registry summary alone.
The registry-defined primary population required baseline FEV1 data and at least one post-baseline visit. The record does not provide a full accounting of missing primary-outcome data or explain how participants with incomplete follow-up contributed to the model. The posted arm counts for the primary and safety outcomes differ, reflecting outcome-specific denominators; the record does not provide enough detail to treat these sets as identical analysis populations.
Several secondary outcomes are listed, but comparative estimates or sponsor analyses are not available for every listed measure. Simple calculations from the posted summaries are unadjusted and may use assumptions different from the trial’s own analysis. For example, the simple event-rate re-calculation uses a Poisson assumption, whereas the sponsor-reported event-rate analysis uses negative binomial regression. They should not be conflated.
The registry describes a specific population, treatment schedule and follow-up period. The posted results do not establish effects outside those conditions. Safety summaries are descriptive counts and do not, on their own, establish causality or account for every aspect of event timing and exposure.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Study of Ataluren in Nonsense Mutation Cystic Fibrosis (ACT CF) — NCT02139306.
- Registry record last updated 2020-05-14; status last verified 2020-05.
- Results first posted 2020-05-14.
- 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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19. Record Summary
This completed Phase 3 randomized, parallel-group study compared oral ataluren with matching placebo in nonsense mutation cystic fibrosis. The primary outcome was change from baseline in ppFEV1 at Week 48, defined using the average of changes at Week 40 and Week 48. The sponsor-reported mixed-model analysis estimated a net mean difference of 0.597 percentage points; its 95% confidence interval included zero, and the reported p-value was 0.534.
The registry also reports secondary pulmonary-exacerbation and safety results. The event-rate comparison used negative binomial regression and had a confidence interval including the no-difference value. The record does not report a multiplicity strategy, a sample-size justification, or complete details of missing-data handling. Secondary results and safety counts should be interpreted in light of those reporting limits and their outcome-specific methods.