Long Term Safety of Tobramycin Inhalation Powder in Patients With Cystic Fibrosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Long Term Safety of Tobramycin Inhalation Powder in Patients With Cystic Fibrosis (NCT01519661), a non-randomized phase 4 study. The primary outcome is Percentage of Participants With Treatment Emergent Adverse Events, Serious Adverse Events (SAEs) and Deaths.

2. Clinical Question

The study was designed to assess long-term safety in people with cystic fibrosis who had chronic pulmonary infection with Pseudomonas aeruginosa. Its primary outcome was a percentage-based account of treatment-emergent adverse events, serious adverse events, and deaths. An event was considered treatment-emergent if it began on or after the first study-drug dose. The registry says events were counted after that point during both on-treatment and off-treatment periods.

The key interpretive distinction is between describing events observed among treated participants and estimating a treatment effect relative to an alternative. Because participants were not randomized to a control treatment and no concurrent comparator is listed, the results describe the experience of the TIP group; they do not establish what would have happened to a comparable group without TIP or with another intervention. The record reports adverse-event counts for the safety set, but does not report a control-group rate or a comparative effect estimate.

3. Trial Design

This was a Phase IV, single-arm, open-label, multicenter trial with non-randomized allocation. The registry lists an enrollment of 157 and identifies Novartis Pharmaceuticals as the sponsor. The study began in 2012-01, reached primary completion in 2014-01, and is marked completed. These design and timing details describe the registry record; they do not by themselves establish the completeness of follow-up for each participant.

The listed intervention was tobramycin inhalation powder, also identified as TBM100. The arm description states that eligible participants were assigned four capsules at 28mg dosage strength, inhaled twice daily in the morning and evening via the T-326 inhaler. The regimen is described as 28 days on treatment followed by 28 days with no study treatment. The record’s arm-description text is truncated after a further statement about the amount of tobramycin per treatment, so no additional regimen detail can be established from that text.

Open-label means that masking was not used, as also stated by the registry. Single-group and non-randomized mean there was no randomized allocation between study treatments. Thus, the adverse-event results are descriptive of the enrolled treated group rather than a randomized comparison. The registry record does not report a separate control arm.

The primary safety population is the safety set, defined as all participants who received at least one dose of study drug. The primary outcome timeframe is 337 days. An event qualified as treatment-emergent based on its onset relative to the first dose, and events after that point were included during both on- and off-treatment periods. The registry record does not report the schedule of safety visits or individual follow-up duration.

The record lists 12 outcome measures, including lung-function measures, sputum microbiology, susceptibility measures, and hospitalization-related outcomes. It does not give results for those outcomes in the registry record for this analysis. The primary safety findings should therefore not be taken as a summary of changes in lung function, bacterial burden, or hospitalization.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety set: The safety set included all participants who received at least one dose of study drug.

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 Percentage of Participants With Treatment Emergent Adverse Events, Serious Adverse Events (SAEs) and Deaths, measured over 337 days.

The primary endpoint is the percentage of participants with treatment-emergent adverse events, serious adverse events, and deaths. It is a safety endpoint: it counts whether participants experienced events after the defined treatment-emergent start point, rather than measuring a change in lung function or a microbiological response. The registry defines treatment-emergent events as those whose onset was on or after the date and time of the first study-drug dose. Events were included during both on-treatment and off-treatment periods after that point.

A percentage is a descriptive way to express how many people in the safety set experienced an event, relative to the participants included in that set. The registry defines the safety set as participants who received at least one dose. For this trial, the listed group had 157 participants; the posted serious-adverse-event count is 49, and the count for other adverse events is 121. Deaths are not reported in the registry record. These event categories should not be conflated: serious adverse events are one category, while the other adverse-event count reflects a separate reported category.

Safety outcomes are used to characterize events observed during exposure and follow-up. They are important for describing the burden and types of events recorded, but a single-group percentage alone cannot establish whether the intervention caused an event or whether its occurrence differs from what would have happened under another treatment. The registry record does not report a comparative safety estimate for this trial.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is expressed as a percentage of participants with events. For a binary outcome, each participant is classified according to whether the event of interest was recorded or was not recorded under the study’s definition. The resulting proportion summarizes the observed frequency in the specified analysis population. In this trial, the defined population is the safety set: all participants who received at least one dose of study drug.

That descriptive proportion answers a limited question: how many participants in the recorded safety population experienced an event during the applicable observation period? It does not, on its own, answer whether treatment caused the event. A causal or comparative question requires an appropriate basis for comparing what happened under the intervention with what would have happened under a relevant alternative. This study has a single group and no randomized comparator, so its event summaries do not provide that comparison.

What does treatment-emergent mean?

The registry uses onset on or after the date and time of the first study-drug dose as the rule for a treatment-emergent event. It includes events after that point during both on-treatment and off-treatment periods. This is a classification rule based on timing relative to treatment initiation. The label does not by itself establish that the study drug caused the event. Events can occur after treatment begins for reasons related to the underlying illness, other care, chance, or the intervention; the single-group record cannot separate these explanations.

The outcome timeframe is 337 days. A fixed stated timeframe helps define the period to which the endpoint refers, but it does not reveal whether all participants were followed for the same duration. The registry record does not report individual follow-up times or participant-level event timing. Those details matter because a simple participant percentage treats the endpoint as whether an event occurred, while differences in time under observation can affect the opportunity for an event to be recorded.

How should the serious-event terms be understood?

The registry lists counts at risk and affected for the group, along with percentages for selected serious adverse-event terms. A participant count and a term percentage are different summaries. A person may experience more than one event or more than one event term, so term-specific percentages are not necessarily exclusive parts of one total. The record does not state whether people could be counted under multiple terms or how repeated events were handled in those term summaries. The reported terms should therefore be read as registry classifications, not as a partition of participants.

The record lists 49 participants affected by serious adverse events and 121 affected by other adverse events, each with 157 at risk. It reports selected serious terms, including infective pulmonary exacerbation of cystic fibrosis at 24.8%. No death count is reported in the registry record. The event counts and term percentages are descriptive; no uncertainty intervals or comparative hypothesis tests are reported for the primary outcome in the information available.

What can a confidence interval add?

In general, a confidence interval expresses statistical uncertainty around an estimate. It can indicate which values remain compatible with the observed data under the assumptions of the method used. A narrow interval conveys greater precision than a wide interval, while neither interval width nor statistical significance establishes causation. The registry record does not report a confidence interval for the primary safety percentages, so their statistical precision cannot be read from an interval estimate in the posted results.

In general, inference from a single-group percentage is also limited by the absence of a contemporaneous comparison. Even a precisely estimated frequency among treated participants would not show how that frequency compares with an alternative. Differences in underlying illness, eligibility, follow-up, and other factors could influence event occurrence, and a single-arm design cannot use randomization to balance such factors across treatment groups.

What is over-dispersion, and does it apply?

In general, over-dispersion refers to more variability in count data than a statistical model assumes. It can matter when outcomes are counts of events, especially if events cluster within people or if participants have different underlying event rates. This primary endpoint is reported as the percentage of participants with events, not as an event-rate model. The registry record does not report a count-model analysis, an over-dispersion assessment, or a method for repeated events. No conclusion about those methods can be drawn from the posted summary.

The record lists sample-size assumptions for a planning illustration: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. Such planning calculations are hypothetical illustrations based on assumptions; they are not observed power and do not change the single-group design of this trial. The record does not report the trial’s own sample-size justification or statistical analysis plan. The planning assumptions do not establish that the study was designed or sized to test a comparative safety hypothesis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures, spanning safety, lung function, sputum microbiology, antimicrobial susceptibility, and hospitalization. When a study evaluates multiple outcomes or multiple analyses, the chance of at least one apparently notable result can increase unless the statistical approach accounts for multiplicity. In general, multiplicity procedures can control that risk, but their use depends on the study’s prespecified questions and analysis plan. The statistical plan and any multiplicity adjustment are not reported in the registry record.

The available information identifies the primary safety outcome and describes several secondary outcomes, but does not provide results for those secondary outcomes or a detailed account of how missing measurements were handled. Missing-data methods are not reported in the registry record. The record also does not report how many participants contributed data at each assessment or whether outcome-specific analysis populations differed.

The safety set includes all participants who received at least one dose. That definition establishes who is eligible for the primary safety summary, but it does not explain how incomplete follow-up, missing event information, or withdrawal was handled. The registry record does not report those details. Deaths are also not reported in the registry record; the unpopulated death count should not be interpreted as a verified zero.

The record lists zero analyses in the available analysis summary. No p-values, confidence intervals, adjusted comparisons, or missing-data sensitivity analyses are included in the information available for this interpretation. The absence of those details limits assessment of inferential precision and robustness. It does not establish which methods were or were not used beyond what the registry record actually reports.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: infective pulmonary exacerbation of cystic fibrosis (24.8%), haemoptysis (3.2%), pneumonia (1.9%), influenza (1.3%), supraventricular tachycardia (0.6%).

The TIP group had 157 participants at risk for the serious-adverse-event summary, of whom 49 were reported as affected. The separate other-adverse-event summary also lists 157 at risk, with 121 affected. These figures describe participants in the treated group; because there is no concurrent control group, they are not comparative risk estimates.

The registry lists infective pulmonary exacerbation of cystic fibrosis at 24.8% as the leading serious adverse-event term. It also lists haemoptysis at 3.2%, pneumonia at 1.9%, influenza at 1.3%, supraventricular tachycardia at 0.6%, and tachyarrhythmia at 0.6%. These are term-specific registry summaries and should not be added together as if each participant could appear in only one category. The record does not report whether participants could have multiple serious-event terms.

Treatment-emergent events were defined by onset on or after the first dose, with events included in on- and off-treatment periods. The stated timeframe was 337 days. A death count is not reported in the registry record. These figures characterize recorded safety events, but do not establish causation, comparative risk, or the event frequency that would have occurred without TIP.

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

The results give a descriptive account of adverse events recorded among participants who received at least one dose of TIP. The registry reports 49 participants with serious adverse events and 121 with other adverse events, each among 157 at risk. It also reports selected serious-event terms and their percentages. These observations are relevant to understanding what was recorded during the stated 337-day timeframe and under the registry’s treatment-emergent definition.

The results do not show that TIP caused every recorded event. The timing rule identifies events beginning on or after the first dose; it is not a causal test. Nor do the figures establish that TIP increased or decreased event frequency relative to another treatment or no treatment. The trial was single-group, open-label, and non-randomized, with no concurrent control group listed. That design means background illness and other influences cannot be separated from treatment effects by a randomized comparison.

The primary endpoint is a percentage-based safety summary, not a measure of treatment efficacy. Although the registry lists secondary outcomes involving lung function, sputum microbiology, and hospitalization, their results are not reported in the information available. No conclusion about those outcomes follows from the adverse-event figures.

The registry record does not report confidence intervals or hypothesis tests for the primary safety outcome, the trial’s statistical analysis plan, or methods for handling missing data. The deaths field is not populated, so deaths are not reported in the registry record; that should not be interpreted as confirmation that none occurred. The findings should therefore be read as the posted descriptive safety record, with uncertainty and comparative interpretation constrained by the information and design available.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of what a single-group safety study can and cannot establish. It records adverse events in a defined safety set and specifies a treatment-emergent rule tied to the first study-drug dose. It also includes both on-treatment and off-treatment periods within its event definition. Those details help define the population and timing behind the reported safety summaries.

At the same time, the design sets a clear boundary on interpretation. A single-arm study can describe the event experience of participants who received the intervention, but it cannot directly estimate a contrast with a concurrent untreated or alternative-treatment group. This matters particularly in cystic fibrosis with chronic pulmonary infection, where the underlying condition itself is part of the context in which adverse events are observed. The registry’s leading serious-event term is infective pulmonary exacerbation of cystic fibrosis, reported at 24.8%; the record does not establish how often such events would occur under another treatment strategy.

The trial also illustrates why event counts, event-term percentages, and causal conclusions are distinct. Counts show how many participants were recorded as affected; term percentages describe selected classifications. Neither substitutes for a controlled comparison or an uncertainty estimate. The absence of reported confidence intervals and analysis details means that the precision and analytic handling of the primary safety results cannot be fully evaluated from the registry record.

Finally, the registry lists a range of secondary outcomes, but results for those measures are not reported in the information available. Keeping the interpretation focused on the posted safety findings avoids treating planned or listed outcome measures as observed results. The statistical contribution is a descriptive safety record, not a comparative estimate of 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 principal limitation for interpretation is the single-arm design. There is no concurrent control group, and allocation was non-randomized. As a result, the event counts cannot be compared within this trial against outcomes under another treatment or no treatment. The open-label design also means masking was not used; the registry record does not report how this may have affected event reporting or classification.

The registry defines the safety set as participants who received at least one dose, and lists 157 participants at risk. It does not report participant-level follow-up duration, losses to follow-up, withdrawals, or the amount of missing safety information. Although the endpoint timeframe is 337 days, that alone does not establish that every participant contributed the same observation time.

The record does not report confidence intervals, hypothesis tests, the statistical analysis plan, or the trial’s sample-size justification. Missing-data methods and handling of repeated or multiple events are also not reported in the registry record. The available description does not clarify whether participants could contribute to more than one serious-event term. Deaths are not reported in the registry record, rather than being documented as absent.

The arm-description text is truncated after its statement about the amount of tobramycin per treatment. The registry lists secondary outcomes, but their results are not reported in the information available for this interpretation. These limitations mean the posted results support a description of reported safety events, but provide limited information about precision, completeness, causal attribution, or outcomes beyond the primary safety measure.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Long Term Safety of Tobramycin Inhalation Powder in Patients With Cystic Fibrosis — NCT01519661.
• Registry record last updated 2015-02-10; status last verified 2015-02.
• Results first posted 2015-02-10.
• 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 identifies NCT01519661 as a completed Phase IV, multicenter, open-label, non-randomized, single-group study of tobramycin inhalation powder in people with cystic fibrosis and chronic pulmonary infection with Pseudomonas aeruginosa. Enrollment was 157. The study began in 2012-01 and reached primary completion in 2014-01.

The primary outcome was the percentage of participants with treatment-emergent adverse events, serious adverse events, and deaths over 337 days. Treatment-emergent events were defined by onset on or after the first study-drug dose and included events during on- and off-treatment periods. The safety set included participants who received at least one dose.

The registry reports 49 participants with serious adverse events and 121 with other adverse events, each among 157 at risk. Selected serious-event terms include infective pulmonary exacerbation of cystic fibrosis at 24.8%. Deaths are not reported in the registry record. With no concurrent comparator, these are descriptive findings for the treated group rather than comparative treatment effects.