Trial of Aeroquin Versus Tobramycin Inhalation Solution (TIS) in Cystic Fibrosis (CF) Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of Aeroquin Versus Tobramycin Inhalation Solution (TIS) in Cystic Fibrosis (CF) Patients (NCT01270347), a randomized phase 3 study. The primary outcome is Number of Participants With Treatment Emergent Adverse Events (TEAEs).

2. Clinical Question

The trial was designed to evaluate safety and efficacy, but the primary outcome posted in the registry is a safety count: the number of participants with treatment-emergent adverse events. An event could be an unfavorable or unintended sign, symptom or disease temporally associated with study-drug use, whether or not it was considered related to the drug. The definition also includes new disease, worsening of an existing illness, increased frequency or intensity of an episodic condition, and a condition first detected after study-drug administration even if it may have been present earlier.

The record describes the participants as stable patients with cystic fibrosis. Its background discusses chronic lower-respiratory-tract infections, including infection with Pseudomonas aeruginosa, and the rationale for antibiotic delivery to the lung. That background explains the clinical context, but it does not establish that every participant had the same infection or that the trial’s primary outcome measured bacterial eradication. The principal posted comparison is about whether participants experienced treatment-emergent adverse events during the stated follow-up, not a direct measure of antimicrobial effect.

3. Trial Design

The registry describes a randomized, open-label, parallel phase 3 trial. Participants were assigned to inhaled levofloxacin solution, marketed in the record as Aeroquin and identified as MP-376, or to tobramycin inhalation solution. The posted arm titles specify levofloxacin inhalation solution 240 mg and tobramycin inhalation solution 300 mg. The record gives an enrollment of 282.

Open-label means the record reports no masking. The registry does not report who knew the assigned treatment or whether outcome assessment was blinded by any other means. Randomization indicates assignment by a randomized process, but the method used to generate or conceal allocation is not reported in the registry record. The parallel model means the record presents separate treatment arms rather than a crossover comparison; further details of treatment sequencing are not reported.

The primary outcome is the number of participants with treatment-emergent adverse events, measured from study start until study end, up to 168 days. The primary outcome population is identified as the Safety Population. The posted primary arm summaries list 90 participants for tobramycin and 182 for levofloxacin; the event counts are 90 and 180, respectively. The registry’s total enrollment and the denominators in particular outcome analyses are not interchangeable: outcome-specific counts can differ, and the record does not explain every such difference.

Secondary outcomes include lung-function measures, categories of relative or percent change in FEV1, Pseudomonas aeruginosa sputum density, and the respiratory domain of the Cystic Fibrosis Questionnaire Revised. The record lists ten secondary outcome measures, while results are posted for eight. The trial start is recorded as 2011-01, primary completion as 2012-10, and status as completed. The registry record does not report the randomization procedure, treatment adherence, detailed visit schedule, or the rationale used to choose the enrollment target.

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.

Core Phase

Reasons for not completing this period:

Extension Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Population

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: Safety population included all participants randomized in the study who received at least 1 dose of Levofloxacin inhalation solution or TIS.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment Emergent Adverse Events (TEAEs), measured over From start of study until end of the study (up to 168 days).

The primary endpoint counts participants who experienced at least one treatment-emergent adverse event during the specified observation period. It is a participant-level count outcome: it records whether a participant had an event, rather than the total number of events or the severity of each event. The registry defines an adverse event broadly as an unfavorable or unintended sign, symptom, or disease temporally associated with study-drug use, regardless of whether it was considered related to the study drug.

This kind of outcome is used to describe the frequency of events arising during treatment and to compare that frequency between assigned groups. It is relevant to safety because events occurring during a trial are important to characterize even when a causal relationship to the study drug has not been established. The outcome does not, by itself, distinguish events caused by treatment from events attributable to the underlying condition or other factors. Nor does it summarize the clinical seriousness, duration, recurrence, or impact of every event. Those questions require additional event-level information.

The timeframe is from study start until the end of the study, up to 168 days. In the posted primary results, the tobramycin arm has 90 participants with events among 90 listed for that outcome, while the levofloxacin arm has 180 among 182. The registry reports a risk-difference estimate of -0.011 for levofloxacin relative to tobramycin, with a 95% confidence interval from -0.026 to 0.004 and an unadjusted p-value of 0.318. These figures describe the posted comparison; they do not establish that events were caused by either treatment or that the treatments have identical safety profiles.

7. Results Posted in the Registry

• Levofloxacin Inhalation Solution 240 mg: 98.9% (180/182) versus 100.0% (90/90) on control; risk difference -1.1 percentage points (95% CI -2.6 to 0.4), risk ratio 0.99 (0.97–1.00); unadjusted two-proportion z-test p = 0.318.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Percent Change From Baseline in Average Expired Flow Over the Middle Half of The FVC Maneuver (FEF25-75)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Levofloxacin Inhalation Solution 240 mg: mean 9.67 versus 4.71 on control; difference 4.97 (95% CI -12.87 to 22.80), standardized effect d = 0.09; z-test p = 0.585.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Levofloxacin Inhalation Solution 240 mg and the control. The interval gives the range of effects that remain compatible with the data.

Percent Change From Baseline in Forced Vital Capacity (FVC)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Levofloxacin Inhalation Solution 240 mg: mean 0.42 versus -1.15 on control; difference 1.57 (95% CI -0.75 to 3.89), standardized effect d = 0.16; z-test p = 0.185.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Levofloxacin Inhalation Solution 240 mg and the control. The interval gives the range of effects that remain compatible with the data.

Change From Baseline in Pseudomonas Aeruginosa Sputum Density

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Levofloxacin Inhalation Solution 240 mg: mean -0.75 versus -1.19 on control; difference 0.44 (95% CI -0.17 to 1.05), standardized effect d = 0.18; z-test p = 0.159.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Levofloxacin Inhalation Solution 240 mg and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes cover several kinds of measurement: lung-function changes, categories of FEV1 response, sputum bacterial density, and the respiratory domain of a cystic-fibrosis questionnaire. This breadth means the secondary findings address related but distinct aspects of the trial. They should not be treated as interchangeable evidence about one single effect. A lung-function measure, a microbiological measure, and a patient-reported respiratory measure capture different outcomes and may have different sources of variability.

The registry lists ten secondary outcome measures and reports results for eight. The continuous results posted in the record include three ANCOVA analyses labelled non-inferiority, as well as group summaries and unadjusted recalculations. The outcome list also includes categories of relative or percent change in FEV1 and categories of change in sputum density and questionnaire score. The record does not provide enough information to explain why results are not posted for every listed secondary outcome.

These results complement the primary safety endpoint but do not determine it. The primary endpoint counts participants with treatment-emergent adverse events; secondary measures address lung function, sputum density, or respiratory status. A pattern in one domain cannot be assumed to explain a pattern in another. Nor can multiple secondary outcomes be taken as independent confirmations when the registry does not report how multiplicity was handled.

Unadjusted secondary results carry less inferential weight than a prespecified primary analysis because they may be among many comparisons and may not account for the trial’s planned covariate adjustment. Repeated testing across outcomes can increase the chance of apparently notable findings even when there is no corresponding underlying effect. The registry does not report a multiplicity strategy, so the strength of evidence from the secondary findings should be considered cautiously. The posted data are best read as a set of outcome-specific observations that may inform further evaluation, not as a definitive overall efficacy conclusion.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percent Change From Baseline in Average Expired Flow Over the Middle Half of The FVC Maneuver (FEF25-75)
• Percent Change From Baseline in Forced Vital Capacity (FVC)
• Number of Participants in Each Category of Relative Change in Percent Predicted FEV1
• Number of Participants in Each Category of Percent Change From Baseline in FEV1
• Change From Baseline in Pseudomonas Aeruginosa Sputum Density
• Number of Participants in Each Category of Change From Baseline in Pseudomonas Aeruginosa Sputum Density
• Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire Revised (CFQ-R)
• Number of Participants in Each Category of Change From Baseline in the Respiratory Domain of CFQ-R

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is a binary participant-level measure: whether a participant had a treatment-emergent adverse event during the study. A risk difference expresses the event risk in one group minus the event risk in the comparison group. In this record, the reported contrast is for levofloxacin relative to tobramycin, with an estimate of -0.011. A negative estimate points toward a lower reported event risk in the levofloxacin group, but the estimate is not a guarantee that the underlying difference is negative. Sampling variation is represented by the confidence interval.

A confidence interval describes uncertainty around an estimate under the statistical model used. The 95% interval for the primary risk difference runs from -0.026 to 0.004. Because it includes zero, the data are compatible with no difference as well as with differences on either side of zero within the interval. This interpretation is about statistical uncertainty, not the probability that a particular treatment is better for an individual. A p-value answers a related but different question: how compatible the data are with a specified null model. The unadjusted p-value for the primary comparison is 0.318. It should not be read as the probability that the treatments are the same or that the result is due to chance.

For continuous secondary outcomes, the record reports least-squares means and standard errors. A least-squares mean is an adjusted group estimate from a model, rather than necessarily the plain arithmetic average of the observed measurements. Standard error describes uncertainty in an estimated mean. It is not the same as the spread of individual participant values. The registry reports ANCOVA analyses for three continuous outcomes, giving least-squares mean differences, confidence intervals, and p-values. ANCOVA compares groups while adjusting for covariates included in the model. Which covariates were used is not reported in the registry record.

Some displayed secondary comparisons are recalculated from posted summary statistics without adjustment. Such a recalculation does not reproduce an ANCOVA model unless all relevant model details and data are available. For example, the posted ANCOVA estimate for FEF25-75 is 4.968, with a 95% confidence interval from -0.653 to 10.590 and p=0.083. The unadjusted recalculation also estimates 4.968, but gives a different confidence interval and p-value. The sponsor’s own analysis takes precedence over that simple recalculation for interpretation of the trial’s reported analysis. This distinction is especially important when the registry labels the reported analyses as non-inferiority analyses.

Non-inferiority asks whether a treatment is not worse than a comparator by more than a prespecified margin. The conclusion depends on the margin, the direction of the contrast, the analysis population, and the confidence-interval decision rule. The margin and the detailed decision rule are not reported in the registry record. Therefore, the posted label and p-value alone do not establish that non-inferiority was demonstrated. A conventional test of whether a difference is zero and a non-inferiority test do not necessarily answer the same question.

Statistical power and sample-size planning are also distinct from the results observed in a completed trial. The registry includes planning illustrations based on fractions of the observed secondary effects, with stated assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation. These are hypothetical planning calculations, not observed power and not evidence that the trial was designed using those assumptions. The trial’s own sample-size justification is not reported in the registry record. Planning based on an observed effect can be unstable because the effect estimate itself is uncertain, and a smaller assumed effect generally requires more participants to detect under otherwise similar assumptions.

General statistical context: when observations are more variable than a simple model allows, standard errors and confidence intervals based on that model can be misleading. For count outcomes, over-dispersion means that counts vary more than a basic count model expects. The primary endpoint is a count of participants with an event, not a count of recurrent events per participant, so over-dispersion of event counts is not directly the structure of this posted endpoint. The registry reports a risk-difference comparison rather than a recurrent-event model.

General statistical context: randomized allocation can support a comparison of assigned groups, but it does not remove all uncertainty or guarantee that every feature of the groups will be balanced in a particular trial. Open-label conduct can also affect reporting, care, or assessment, depending on the outcome and trial procedures. The registry identifies the study as open-label but does not report procedures intended to reduce such influences. These design considerations inform interpretation; they do not allow a conclusion about whether bias occurred in this trial.

Finally, outcome-specific denominators matter. The primary safety summaries list 90 participants in the tobramycin arm and 182 in the levofloxacin arm, while the continuous secondary results use other denominators. This may reflect different analysis populations or availability of measurements, but the reasons are not reported in the registry record. Without those details, the safest interpretation is to read each outcome with its own posted denominator and avoid assuming that every analysis includes the same participants.

11. Confidence Intervals and Precision

The primary risk-difference estimate is -0.011, with a 95% confidence interval from -0.026 to 0.004. The interval includes zero, so the posted primary comparison does not pin down the direction of the difference. It encompasses a negative contrast and a positive contrast under the reported scale. The point estimate is only one plausible estimate within that uncertainty; it should not be treated as an exact description of the underlying event risks.

Precision concerns how tightly the data locate an estimate. A narrower interval generally reflects greater precision, while a wider interval leaves more uncertainty about the magnitude and direction. The primary interval’s endpoints are relatively close to zero, but this does not establish equivalence. Equivalence requires a prespecified range of differences judged acceptable and an analysis showing that uncertainty lies within that range. The registry does not report such an equivalence margin.

The secondary ANCOVA intervals also convey uncertainty. For FEF25-75, the reported 95% interval is -0.653 to 10.590; for FVC it is -0.272 to 3.411; and for sputum density it is -0.01 to 0.88. Each interval should be read in the scale and direction of its outcome, and alongside the analysis method and any prespecified criterion. The registry labels these analyses as non-inferiority, but does not report the margin needed to assess that claim independently.

Confidence intervals do not account for every possible limitation. Their interpretation depends on the model, outcome definition, participant data used, and analysis choices. Missing-data handling, covariate specifications, and multiplicity procedures are not reported in the registry record. Consequently, the intervals describe statistical uncertainty under the reported analyses, not uncertainty from every design or reporting issue. The primary result is informative about the recorded comparison, but it does not show that the two treatments have precisely identical risks.

12. Multiplicity, Missing Data and Analysis Populations

The registry does not report whether the analysis plan controlled for multiple comparisons across the primary and secondary outcomes, or across the several categories of change listed among the secondary measures. When many outcomes or contrasts are examined, the chance of at least one apparently notable result can increase. A prespecified multiplicity approach can address that concern, but no such approach is described in the registry record. The posted unadjusted p-values should therefore be interpreted as outcome-specific values, not as evidence that the entire family of comparisons was controlled.

The record does not report how missing outcome data were handled. It also does not explain why the denominators differ between the primary safety endpoint and secondary continuous outcomes. Different denominators could reflect outcome availability or analysis-population definitions, but the reason is not reported in the registry record. Without further detail, it is not possible to assess whether missingness could have affected the estimates or whether a particular method was used to address it.

The primary outcome identifies the Safety Population. The registry does not describe the population definitions for every secondary analysis, or state whether analyses followed intention-to-treat, per-protocol, or another approach. This is especially relevant for non-inferiority analyses, where conclusions can depend on the analysis population and how protocol deviations are handled. The record labels the reported secondary ANCOVA analyses as non-inferiority, but does not report the margin, covariates, or full analysis plan.

Interim analyses and any associated statistical decision rules are not reported in the registry record. The trial’s sample-size justification is also not reported. These omissions do not invalidate the posted findings, but they limit independent assessment of whether the analyses followed a prespecified plan and how much emphasis should be placed on each result. The sample-size illustrations based on observed effects are planning scenarios, not evidence of the trial’s original design or observed power.

13. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: disease progression (26.7%), bronchopneumonia (2.2%), haemoptysis (2.2%), pneumonia (1.1%), small intestinal obstruction (1.1%).

The serious adverse event summaries distinguish serious events from the broader primary outcome of participants with any treatment-emergent adverse event. In the core phase, the registry lists serious adverse events for 29 participants among 90 at risk in the tobramycin group and 40 among 182 at risk in the Aeroquin group. In the extension phase, it lists 22 among 88 at risk for Aeroquin. The record lists no deaths in these groups.

These figures should not be read as a direct randomized comparison across all three entries. The extension-phase entry is a separate phase and does not have a tobramycin extension group listed in these safety summaries. The registry does not describe the extension-phase eligibility or the relationship between participants in the core and extension phases. The serious-event counts also do not establish that study treatment caused the events.

The registry lists serious-event terms including Disease progression (26.7%), Bronchopneumonia (2.2%), Haemoptysis (2.2%), Pneumonia (1.1%), Small intestinal obstruction (1.1%), and Pneumothorax (1.1%). The record does not specify in this summary the denominator underlying each displayed percentage, so they should be read as listed rather than converted into counts or compared as if they were risks in the randomized arms. Serious-event listings provide context about the types of events recorded; they do not replace the primary all-event endpoint.

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

The primary result describes treatment-emergent adverse events recorded during the study period. The registry reports events in 90 of 90 participants in the tobramycin arm and 180 of 182 participants in the levofloxacin arm, with a risk-difference estimate of -0.011 and a 95% confidence interval from -0.026 to 0.004. The interval includes zero, so the data do not establish a clear difference in either direction.

This result does not establish that the treatments have identical safety profiles. A failure to show a clear difference is not the same as proof of equivalence or non-inferiority. Such conclusions require an appropriate prespecified margin and analysis. The margin for the reported non-inferiority secondary analyses is not reported in the registry record, and the primary endpoint is presented as a safety count rather than an equivalence analysis.

The outcome also does not establish causation. The registry definition includes events temporally associated with study-drug use whether or not considered related to the drug. An event may reflect the underlying disease, another exposure, or other factors. The broad count does not indicate how many events were judged treatment-related, their duration, or their severity. Serious-event listings add information about seriousness and terms, but they do not determine cause.

Likewise, the primary safety endpoint does not by itself answer whether the treatments differ in efficacy. The listed secondary measures address lung function, sputum density, and respiratory quality of life, but interpretation is limited by the lack of reported detail on multiplicity, missing data, and analysis populations. The registry record is one source of trial results, and its posted estimates should be understood in the context of the methods and reporting details available there. No treatment recommendation follows from these statistics alone.

15. Why This Trial Matters Statistically

This trial illustrates why a clinical-trial result should be read through its endpoint, design, and uncertainty rather than through a single point estimate. The primary measure counts participants with at least one treatment-emergent adverse event. That broad safety measure is clinically relevant, but it combines events that can differ substantially in severity, duration, and cause. It is not a direct measure of treatment-related harm unless the relationship to treatment is separately assessed.

The trial also shows the distinction between an estimate and the evidence supporting a decision. The primary risk difference is close to zero, but its confidence interval includes values on both sides of zero. That is not proof of equal risks. A claim of equivalence or non-inferiority requires a prespecified decision framework, and the relevant margin is not reported for the secondary analyses labelled non-inferiority.

Its secondary outcomes illustrate another recurring statistical issue: several outcomes may be measured across different domains and analyzed using different methods. The registry reports ANCOVA analyses as well as simple unadjusted recalculations. Adjusted and unadjusted estimates answer related but not necessarily identical questions, and the sponsor’s reported analysis is the principal analysis to consider. Multiple testing can also affect how much weight to place on individual secondary findings; a multiplicity strategy is not reported.

Finally, the record makes clear that the enrollment total is not the denominator for every outcome. The primary and secondary analyses use outcome-specific populations and counts, with limited reporting on the reasons for differences. Reading each estimate with its own denominator and confidence interval is essential. These features make the trial a useful example of interpreting safety counts, adjusted secondary analyses, non-inferiority labels, and incomplete reporting without turning uncertainty into a claim of no difference.

16. 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 registry record leaves several trial-specific details unavailable for evaluating the posted comparisons. Although the study is identified as randomized, the sequence-generation and allocation-concealment methods are not reported. The study is open-label, and the record does not describe whether any outcome assessments were blinded. These omissions limit assessment of how assignment and outcome reporting were protected against bias.

The primary outcome is broad and counts participants with treatment-emergent adverse events regardless of whether the events were considered related to study drug. The posted summary does not give event-level severity, duration, recurrence, or attribution for the full set of events. It therefore cannot show whether groups differed in particular kinds of non-serious events or in treatment-related events specifically. Serious-event summaries are reported separately, and the extension entry is not a direct randomized comparison with a concurrent tobramycin extension group in the listed data.

Outcome denominators vary. The record does not explain the differences between the primary safety population and the secondary analysis counts, or report missing-data methods. The covariates used in the reported ANCOVA analyses are not stated. For analyses labelled non-inferiority, the margin and full decision criteria are not reported. The sample-size justification and any interim analyses are also not reported in the registry record.

The registry lists ten secondary outcomes and posts results for eight. It does not report a multiplicity adjustment or explain the absence of results for the remaining listed measures. Consequently, secondary findings warrant caution, particularly when considered as a group. These reporting limits do not negate the observed results, but they constrain what can be concluded about precision, bias, and the strength of evidence for differences between treatments.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Trial of Aeroquin Versus Tobramycin Inhalation Solution (TIS) in Cystic Fibrosis (CF) Patients — NCT01270347.
• Registry record last updated 2024-12-13; status last verified 2024-11.
• Results first posted 2024-05-21.
• 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.

20. Record Summary

The completed phase 3 study was a randomized, open-label, parallel comparison of inhaled levofloxacin solution, identified as Aeroquin or MP-376, with tobramycin inhalation solution in stable patients with cystic fibrosis. The registry records enrollment of 282 and gives a primary follow-up period from study start until study end, up to 168 days.

The primary safety endpoint was the number of participants with treatment-emergent adverse events. The posted comparison gives a risk difference of -0.011 for levofloxacin relative to tobramycin, with a 95% confidence interval from -0.026 to 0.004 and unadjusted p=0.318. The interval includes zero and does not establish a clear difference.

Secondary outcomes include lung function, sputum density, FEV1 response categories, and respiratory questionnaire measures. Three reported continuous analyses are identified as ANCOVA non-inferiority analyses, but the registry does not report the margins or full analysis details. Multiplicity handling, missing-data methods, and the sample-size justification are not reported in the registry record.