This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
RESPIRE 2 was a randomized, quadruple-masked, parallel phase 3 trial evaluating ciprofloxacin dry powder for inhalation in participants with non-cystic fibrosis bronchiectasis. The registry reports four arms, 521 participants enrolled, two primary time-to-event endpoints, and formal statistical analyses for both primary comparisons.
| Feature | RESPIRE 2 |
|---|---|
| Trial name | RESPIRE 2 |
| NCT ID | NCT02106832 |
| Therapeutic area | Pulmonology |
| Condition | Bronchiectasis |
| Population description | Non-cystic fibrosis bronchiectasis (Non-CF BE) |
| Phase | Phase 3 |
| Status | COMPLETED |
| Allocation | RANDOMIZED |
| Design model | PARALLEL |
| Masking | QUADRUPLE |
| Primary purpose | TREATMENT |
| Enrollment | 521.0 |
| Arms | 4 |
| Lead sponsor | Bayer |
| Sponsor type | INDUSTRY |
| Start | 2014-04-30 |
| Primary completion | 2016-09-13 |
2. Clinical Question
The central statistical question was whether ciprofloxacin dry powder for inhalation changed the time to first qualifying exacerbation within 48 weeks compared with pooled placebo in participants with non-cystic fibrosis bronchiectasis.
Population
Participants with bronchiectasis described in the trial as non-cystic fibrosis bronchiectasis (Non-CF BE).
Intervention
Ciprofloxacin (BAYQ3939) dry powder for inhalation. The registry identifies two ciprofloxacin reporting groups, including Cipro 28 Days on/Off and Cipro 14 Days on/Off.
Comparator
Pooled placebo, with the registry defining separate placebo and ciprofloxacin arms within the four-arm parallel design.
Primary question
Does ciprofloxacin DPI increase the time until the first qualifying exacerbation event within 48 weeks relative to pooled placebo?
3. Trial Design
RESPIRE 2 used randomized allocation, a parallel design, and quadruple masking. The registry identifies four intervention arms: two ciprofloxacin DPI arms and two placebo arms. The primary purpose was treatment.
Cipro 28 Days on/Off
- Ciprofloxacin (BAYQ3939) dry powder for inhalation
- Primary comparison against pooled placebo
- Primary endpoint: time to first exacerbation event within 48 weeks
Cipro 14 Days on/Off
- Ciprofloxacin (BAYQ3939) dry powder for inhalation
- Primary comparison against pooled placebo
- Primary endpoint: time to first exacerbation event within 48 weeks
Pooled placebo reporting group
- Placebo
- Comparator for the two primary analyses
- Pooled for the reported primary treatment comparisons
Registry intervention structure
- Four total arms
- Two ciprofloxacin DPI entries
- Two placebo entries
4. Trial Timeline
Trial start
The registry lists April 30, 2014 as the study start date.
Primary completion
The registry lists September 13, 2016 as the primary completion date.
Results posted
ClinicalTrials.gov reports that results have been posted, including nine outcome measures and two formal statistical analyses.
5. Primary Endpoints
Both registered primary endpoints are time-to-event outcomes measured up to Week 48. The event definition is the same for both comparisons.
| Endpoint | Registry definition | Time frame |
|---|---|---|
| Time to First Exacerbation Event Within 48 Weeks - Cipro 28 vs. Pooled Placebo | Time to first exacerbation was defined as the time from randomization until the visit at which the first qualifying exacerbation is recorded by the investigator. Exacerbation events are defined as exacerbations with systemic antibiotic use and presence of fever or malaise / fatigue and worsening of at least three signs/symptoms. | Up to Week 48 |
| Time to First Exacerbation Event Within 48 Weeks - Cipro 14 vs. Pooled Placebo | Time to first exacerbation was defined as the time from randomization until the visit at which the first qualifying exacerbation is recorded by the investigator. Exacerbation events are defined as exacerbations with systemic antibiotic use and presence of fever or malaise / fatigue and worsening of at least three signs/symptoms. | Up to Week 48 |
What counts as the event?
The registry definition requires more than a nonspecific worsening of symptoms. A qualifying exacerbation requires systemic antibiotic use together with fever or malaise / fatigue and worsening of at least three signs or symptoms. The time origin is randomization, and the event time is the visit at which the first qualifying exacerbation is recorded by the investigator.
The statistical target is not simply the proportion of participants who experienced an exacerbation. The endpoint incorporates when the first qualifying event occurred, allowing participants with different amounts of event-free follow-up to contribute information appropriately.
6. Statistical Methodology
Analysis population
The reported efficacy analyses used the Full Analysis Set (FAS), defined in the registry as participants who were randomized. This is aligned with an intention-to-treat principle: treatment comparisons remain anchored to randomized assignment rather than being restricted to participants who completed treatment.
Cox proportional-hazards model
The registry states that the hazard ratio and confidence interval were calculated using a Cox proportional hazards model. The treatment comparison was made between the specified ciprofloxacin reporting group and pooled placebo.
An HR below 1 indicates a lower estimated instantaneous event rate in the ciprofloxacin group under the fitted model. An HR above 1 indicates a higher estimated instantaneous event rate. The HR is a relative time-to-event measure, not a percentage of participants who experience the event.
Wald-type testing
The registry reports a Wald-type test for the p-value. A Wald test evaluates the estimated treatment effect relative to its estimated standard error. In a large-sample setting, this standardized quantity can be compared with a reference normal distribution.
For a hazard-ratio analysis, the Wald calculation is typically formulated on the log-hazard-ratio scale because the logarithm maps the positive HR scale to an unrestricted real-valued scale.
Confidence intervals
The two primary analyses use different reported confidence levels: 99.9% for the Cipro 28 comparison and 95.1% for the Cipro 14 comparison. Both intervals are explicitly described as two-sided in the registry data.
Superiority hypothesis
The registry identifies the hypothesis type for both primary analyses as superiority. This means the statistical question was whether the treatment comparison demonstrated evidence of a difference in the specified direction rather than whether ciprofloxacin met a non-inferiority margin.
7. Primary Result: Cipro 28 vs. Pooled Placebo
The first primary analysis evaluated time to first exacerbation event within 48 weeks for the Cipro 28 Days on/Off reporting group versus pooled placebo.
Hazard ratio for time to first exacerbation
99.9% two-sided CI: 0.3928–1.2698
Wald-type P-value: 0.0511
| Element | Reported result |
|---|---|
| Endpoint | Time to First Exacerbation Event Within 48 Weeks - Cipro 28 vs. Pooled Placebo |
| Time frame | Up to Week 48 |
| Analysis population | Full analysis set (FAS); participants who were randomized |
| Comparison | Cipro 28 Days on/Off vs Pooled Placebo |
| Effect measure | Hazard Ratio (HR) |
| Estimate | 0.7062 |
| Confidence interval | 99.9% two-sided CI: 0.3928–1.2698 |
| Statistical test | Wald-type test |
| P-value | 0.0511 |
| Hypothesis type | Superiority |
The estimated hazard ratio of 0.7062 means that, under the fitted Cox model, the estimated instantaneous rate of a first qualifying exacerbation in the Cipro 28 reporting group was approximately 70.62% of the corresponding rate in pooled placebo. Equivalently, the point estimate corresponds to an approximately 29.38% lower estimated hazard, because 1 − 0.7062 = 0.2938.
The HR does not mean that 29.38% fewer participants necessarily experienced an exacerbation, nor does it mean that each individual participant had exactly a 29.38% reduction in risk. It is a model-based relative measure of event hazard over the analyzed follow-up.
The 99.9% confidence interval of 0.3928–1.2698 is wide relative to the point estimate. It spans 1, meaning that the interval includes values corresponding to a lower estimated hazard as well as values corresponding to a higher estimated hazard. The interval therefore communicates substantial statistical uncertainty around the point estimate.
The P-value of 0.0511 is evidence from the reported Wald-type test against the relevant null hypothesis; it is not a measure of the size or clinical importance of the hazard ratio. A p-value does not tell us that the treatment effect is "5.11%" or that there is a 5.11% probability that the null hypothesis is true.
The registry's analysis specifies a Cox proportional-hazards model, so interpretation of the single HR also depends on the model's proportional-hazards framework. The reported analysis population was the FAS of randomized participants, preserving the randomized treatment assignment for the efficacy comparison.
8. Primary Result: Cipro 14 vs. Pooled Placebo
The second primary analysis evaluated time to first exacerbation event within 48 weeks for the Cipro 14 Days on/Off reporting group versus pooled placebo.
Hazard ratio for time to first exacerbation
95.1% two-sided CI: 0.6206–1.2090
Wald-type P-value: 0.3965
| Element | Reported result |
|---|---|
| Endpoint | Time to First Exacerbation Event Within 48 Weeks - Cipro 14 vs. Pooled Placebo |
| Time frame | Up to Week 48 |
| Analysis population | Full analysis set (FAS); participants who were randomized |
| Comparison | Cipro 14 Days on/Off vs Pooled Placebo |
| Effect measure | Hazard Ratio (HR) |
| Estimate | 0.8662 |
| Confidence interval | 95.1% two-sided CI: 0.6206–1.2090 |
| Statistical test | Wald-type test |
| P-value | 0.3965 |
| Hypothesis type | Superiority |
The estimated hazard ratio of 0.8662 means that, under the fitted Cox model, the estimated instantaneous rate of a first qualifying exacerbation in the Cipro 14 reporting group was approximately 86.62% of the corresponding rate in pooled placebo. The point estimate therefore corresponds to an approximately 13.38% lower estimated hazard, because 1 − 0.8662 = 0.1338.
Again, the HR is not a direct estimate of the percentage of participants who avoided an exacerbation. It is a relative time-to-event measure and should not be interpreted as an individual-level probability.
The 95.1% confidence interval of 0.6206–1.2090 includes 1. This indicates that the data, under the reported model and confidence-interval procedure, are compatible with a range of treatment effects that includes both a lower and a higher hazard relative to pooled placebo.
The P-value of 0.3965 is the result of the reported Wald-type test. It does not quantify the magnitude of the observed HR and should not be interpreted as a probability that the treatment is ineffective or effective.
As with the Cipro 28 analysis, the HR comes from a Cox proportional-hazards model and therefore has the usual model-based interpretation. The analysis population was the randomized FAS, consistent with an intention-to-treat approach.
9. Comparing the Two Primary Estimates
| Primary comparison | HR | Confidence interval | P-value |
|---|---|---|---|
| Cipro 28 vs Pooled Placebo | 0.7062 | 99.9% CI 0.3928–1.2698 | 0.0511 |
| Cipro 14 vs Pooled Placebo | 0.8662 | 95.1% CI 0.6206–1.2090 | 0.3965 |
The point estimates differ: 0.7062 for Cipro 28 and 0.8662 for Cipro 14. The corresponding confidence intervals both include 1. These estimates should be read as two separate randomized treatment comparisons against the pooled placebo reporting group rather than as a formal statistical comparison between the two ciprofloxacin schedules.
A difference between two p-values does not establish that the corresponding treatment effects differ. A formal comparison of effects would require an appropriate interaction or direct contrast in a model designed to test that question. The ClinicalTrials.gov record does not report such a comparison.
10. Statistical Methods Explained
Why was a time-to-event endpoint used?
The primary outcome was defined as time from randomization until the first qualifying exacerbation, rather than simply whether an exacerbation occurred. This preserves information about the timing of the event and allows participants who remain event-free through their available follow-up to contribute censored time.
What does a hazard ratio of 0.7062 mean?
A hazard ratio of 0.7062 is a relative measure from the fitted Cox model. At the level of the point estimate, the modeled instantaneous event rate is about 70.62% of that in the comparator, corresponding to an approximately 29.38% lower estimated hazard. It does not mean that exactly 29.38% fewer participants had an exacerbation.
Why does the confidence interval matter?
The point estimate is only one estimate from the observed data. The confidence interval describes statistical uncertainty around that estimate under the specified model and confidence-level procedure. For Cipro 28, the 99.9% interval is 0.3928–1.2698. For Cipro 14, the 95.1% interval is 0.6206–1.2090. Both intervals include 1.
Why was a Wald-type test used?
The registry reports a Wald-type test for the p-value. Conceptually, the test standardizes the estimated treatment effect by its estimated standard error. The resulting standardized statistic is then evaluated against an appropriate reference distribution.
Why is the analysis population important?
The primary analyses used the Full Analysis Set, which the registry defines as participants who were randomized. An analysis based on randomized assignment helps preserve the treatment comparison established by randomization and avoids redefining the efficacy population solely according to treatment exposure or completion.
What does "superiority" mean here?
The registry identifies both primary analyses as superiority tests. The question is therefore whether the ciprofloxacin comparison provides evidence of a treatment difference relative to pooled placebo. This is distinct from non-inferiority testing, where a prespecified margin determines whether an observed difference is sufficiently small to retain a non-inferiority conclusion.
Does a confidence interval crossing 1 prove there is no effect?
No. A confidence interval containing 1 means that the specified confidence interval includes the null hazard ratio. It does not prove that the true effect is exactly 1, nor does it establish that all clinically meaningful effects have been excluded. The width and location of the interval are both important for understanding the information provided by the study.
11. Intention-to-Treat Analysis and the Full Analysis Set
The registry defines the Full Analysis Set as including participants who were randomized. This is important because randomization establishes the treatment groups whose outcomes are being compared.
Why randomization matters
Randomization provides the foundation for comparing outcomes between assigned treatment groups without choosing participants for analysis based on their subsequent outcomes.
Why FAS matters
Using randomized participants for the primary efficacy analysis keeps the analysis aligned with the treatment assignment created by the randomized design.
This does not eliminate every source of uncertainty. Missing follow-up, censoring, treatment exposure, and the assumptions of the time-to-event model can still affect interpretation. The ClinicalTrials.gov record does not provide additional details about missing-data or imputation procedures, so no such procedure is attributed to the trial here.
12. Kaplan-Meier Estimation and Censoring
The registry identifies the primary endpoints as time-to-event outcomes and reports Cox proportional-hazards modeling. For this type of endpoint, Kaplan-Meier estimation is a standard descriptive framework for showing the estimated probability of remaining event-free over time.
For a time-to-first-exacerbation endpoint, the corresponding event-free survival function can be interpreted as the estimated probability of remaining free of the first qualifying exacerbation beyond time t.
Censoring allows participants who have not experienced the qualifying event by the end of their observed follow-up to contribute information up to their censoring time. A valid time-to-event analysis depends on appropriate handling and interpretation of these censored observations.
13. Hazard Ratios and the Proportional-Hazards Framework
The Cox model expresses the treatment comparison through a hazard ratio. The hazard is an instantaneous event-rate concept conditional on remaining event-free up to a given time; it is not the same quantity as cumulative incidence or absolute event probability.
For a binary treatment indicator, exp(β) represents the hazard ratio associated with treatment relative to the reference group under the proportional-hazards model.
A single reported HR summarizes the relative hazard according to the model. If the proportional-hazards relationship is substantially inappropriate over time, a single HR may not fully describe how treatment effects evolve. The ClinicalTrials.gov record does not report a separate assessment of the proportional-hazards assumption.
14. Confidence Intervals and Statistical Precision
The two primary analyses illustrate why confidence-interval level and interval width should be read together with the point estimate.
| Comparison | Point estimate | Confidence level | Lower | Upper |
|---|---|---|---|---|
| Cipro 28 vs Pooled Placebo | 0.7062 | 99.9% | 0.3928 | 1.2698 |
| Cipro 14 vs Pooled Placebo | 0.8662 | 95.1% | 0.6206 | 1.2090 |
The 99.9% interval for Cipro 28 is intentionally a very high-confidence interval and is correspondingly broad. It extends from 0.3928 to 1.2698. The Cipro 14 interval extends from 0.6206 to 1.2090. Neither interval is a range of individual patient outcomes; both quantify uncertainty around the estimated treatment effect under the stated statistical framework.
15. P-Values and Wald Testing
The registry reports P-values of 0.0511 and 0.3965 from Wald-type tests for the two primary analyses.
P-value
A p-value measures the compatibility of the observed test statistic with the null hypothesis under the specified testing framework. It is not a measure of treatment-effect magnitude.
Wald statistic
A Wald-type test uses the estimated effect relative to its estimated uncertainty. It therefore depends on both the point estimate and its standard error.
The two p-values should not be interpreted as direct probabilities that the respective null hypotheses are true. They also should not be converted into statements about the probability that a participant benefits from treatment.
16. Multiplicity and the Two Primary Analyses
RESPIRE 2 has two registered primary endpoints, both comparing a ciprofloxacin reporting group with pooled placebo. The ClinicalTrials.gov record identifies both as superiority analyses and report two formal statistical analyses.
| Analysis | Role | Reported test | Effect measure |
|---|---|---|---|
| Cipro 28 vs Pooled Placebo | Primary | Wald-type test | Hazard ratio |
| Cipro 14 vs Pooled Placebo | Primary | Wald-type test | Hazard ratio |
The ClinicalTrials.gov record does not provide the full multiplicity-control procedure, alpha allocation, hierarchical testing sequence, or a prespecified familywise-error strategy. Those details should not be inferred from the reported p-values alone.
17. Safety Results
The registry data provide serious adverse events by arm as affected participants over participants at risk. The ClinicalTrials.gov record is therefore reported exactly in that form rather than converted into percentages.
| Reporting group | Serious adverse events affected | Participants at risk |
|---|---|---|
| Ciprofloxacin DPI 28 Days on/Off | 28 | 171 |
| Ciprofloxacin DPI 14 Days on/Off | 45 | 174 |
| Pooled Placebo | 41 | 174 |
These counts describe participants affected by serious adverse events relative to the number at risk in each registry-reported reporting group. They are a safety summary and should not be treated as an efficacy endpoint or combined with the time-to-first-exacerbation hazard ratios.
18. What the Primary Results Do — and Do Not — Establish
The reported HR of 0.7062 is below 1, so its point estimate corresponds to a lower estimated hazard of first qualifying exacerbation relative to pooled placebo. However, the reported 99.9% CI of 0.3928–1.2698 includes 1, and the Wald-type p-value is 0.0511. The point estimate therefore should not be treated as if it were a precise estimate of the true treatment effect.
The reported HR of 0.8662 is also below 1, corresponding to a lower estimated hazard at the point-estimate level. Its 95.1% CI of 0.6206–1.2090 includes 1, and the Wald-type p-value is 0.3965. The estimate therefore carries substantial uncertainty relative to the null value.
The ClinicalTrials.gov record does not provide median time to first exacerbation, Kaplan-Meier event-free probabilities, numbers of first events, absolute risk differences, subgroup estimates, or a formal comparison of the two ciprofloxacin schedules. None of these quantities is inferred here.
19. Limitations
- Limited reported numerical detail: the ClinicalTrials.gov record contains the two primary HR estimates, confidence intervals, and p-values, but do not provide median time to first exacerbation, event counts, or time-specific Kaplan-Meier estimates.
- Four-arm structure versus pooled analysis: the trial has four registered arms, while the reported primary comparisons use pooled placebo as the comparator.
- Registry analysis-note discrepancy: the analysis notes posted on ClinicalTrials.gov for the Cipro 14 endpoint refer to "Cipro 28/Pooled Placebo," while the endpoint and groups-compared fields identify Cipro 14 versus pooled placebo.
- Proportional-hazards assumption: the reported HRs come from Cox proportional-hazards models. The ClinicalTrials.gov record does not report a separate assessment of whether the proportional-hazards assumption was satisfied.
- Multiplicity information: the ClinicalTrials.gov record does not specify the complete multiplicity-control strategy for the two primary analyses.
- Missing-data procedures: the ClinicalTrials.gov record does not report a specific imputation or missing-data strategy, so none is attributed to the trial.
- Subgroup information: no subgroup statistical analyses are included in the ClinicalTrials.gov recordset, so treatment-effect heterogeneity cannot be assessed from this record.
- Safety detail: only the registry-reported serious-adverse-event affected/at-risk counts are reported here; broader adverse-event summaries are not added.
- External validity: the ClinicalTrials.gov record identifies bronchiectasis and non-cystic fibrosis bronchiectasis but do not provide a detailed baseline-characteristics table, so broader generalizability cannot be evaluated from the ClinicalTrials.gov record alone.
20. Why This Trial Matters Statistically
RESPIRE 2 is a useful teaching case because the registry results connect a randomized, quadruple-masked, four-arm design with two prespecified time-to-event comparisons. The analysis illustrates how a clinical question about delaying a first exacerbation is translated into a hazard ratio and tested with a Wald-type procedure.
| Concept | How it appears in RESPIRE 2 |
|---|---|
| Randomization | The trial uses randomized allocation. |
| Blinding | The registry identifies quadruple masking. |
| Parallel design | The design model is parallel. |
| Time-to-event endpoint | Both registered primary endpoints measure time to first exacerbation within 48 weeks. |
| Intention-to-treat principle | The FAS includes participants who were randomized. |
| Kaplan-Meier estimation | A natural descriptive framework for the registered time-to-event endpoints. |
| Hazard ratio | The primary effect measure reported for both analyses. |
| Wald / z-test | The registry reports a Wald-type test for each primary p-value. |
| Confidence intervals | The two analyses report two-sided 99.9% and 95.1% confidence intervals. |
| Superiority testing | Both primary analyses are identified as superiority hypotheses. |
| Pooled comparator | Both ciprofloxacin reporting groups are compared with pooled placebo. |
21. Statistical Methods Explained: A Practical Reading Guide
Start with the endpoint
The endpoint is time to the first qualifying exacerbation, not simply whether an exacerbation ever occurred.
Then identify the estimand
The reported estimand is a hazard ratio from a Cox proportional-hazards model comparing the ciprofloxacin reporting group with pooled placebo.
Then inspect uncertainty
The confidence interval shows how precisely the treatment effect was estimated under the reported model and confidence-level procedure.
Then inspect the test
The Wald-type p-value summarizes the statistical test; it should not be mistaken for a measure of effect size.
A disciplined reading of the results therefore moves from endpoint → analysis population → model → effect estimate → confidence interval → hypothesis test. This prevents a p-value from becoming the sole description of the trial's evidence.
22. Related Tutorials
Learn more about the methods used in this trial:
23. Related Calculators
24. Sources
- ClinicalTrials.gov: RESPIRE 2, NCT02106832.
- PubMed record: PMID 29371384.
- PubMed record: PMID 28495619.
Continue with the underlying statistical methods
Explore the statistical concepts that connect randomized clinical-trial design with time-to-event analysis, hazard ratios, confidence intervals, and hypothesis testing.
25. Record Summary
RESPIRE 2 provides a clear example of randomized time-to-event analysis in a four-arm, quadruple-masked phase 3 trial. The two registered primary endpoints measured time to first qualifying exacerbation within 48 weeks and were analyzed in the Full Analysis Set using Cox proportional-hazards models, with hazard ratios and two-sided confidence intervals and Wald-type p-values. The Cipro 28 comparison produced an HR of 0.7062 with a 99.9% CI of 0.3928–1.2698 and P-value of 0.0511; the Cipro 14 comparison produced an HR of 0.8662 with a 95.1% CI of 0.6206–1.2090 and P-value of 0.3965.