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 Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis (NCT00669331), a randomized phase 3 study. The primary outcome is Rate of Graded Pulmonary Exacerbations.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00669331 |
| Phase | Phase 3 |
| Condition | Bronchiectasis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 485 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Syntara |
| Results posted | Yes |
2. Clinical Question
Population
People with non-cystic fibrosis bronchiectasis were the intended study population. The primary-outcome population is described as randomized and treated, and the record says this was referred to as the ITT population in the trial. The registry record does not provide further eligibility criteria or participant characteristics in the information available for this analysis.
Intervention
The intervention was inhaled mannitol 400mg. The study purpose was to examine the efficacy and safety of treatment over 52 weeks, described in the record as 12 months. The background rationale discusses mucus clearance and the potential role of a mucoactive therapy; those are the study's rationale, not evidence of a treatment effect in this trial.
Comparator
The comparison group received matched control described as inhaled mannitol 50mg. It was therefore not described as a no-treatment group. The registry record identifies a randomized, parallel-group comparison and quadruple masking, but does not specify the identities of all masked parties.
Primary question
The primary outcome asks whether the rate of graded pulmonary exacerbation events per year differs between the treatment groups over 52 weeks. A graded event required worsening signs and symptoms requiring a treatment change. The registry record gives the endpoint definition but does not report a single treatment-group estimate, a between-group effect estimate, or an uncertainty interval for the primary comparison. The direction and precision of any difference therefore cannot be described from the primary-outcome information recorded.
3. Trial Design
This was a Phase III, randomized, parallel-group, controlled, double-blind study, with masking recorded as quadruple. It investigated inhaled mannitol over 12 months in people with bronchiectasis. The registry lists 485 participants as the enrollment and marks the study completed. The study start is recorded as 2009-11 and primary completion as 2014-01.
The intervention arm received inhaled mannitol 400mg. The matched control arm received inhaled mannitol 50mg. This active low-dose comparator matters when interpreting the research question: the comparison concerns the assigned regimens, not mannitol versus an explicitly described inert placebo. The record does not provide further details about treatment administration, adherence, treatment discontinuation, or the masking procedures.
The primary endpoint was the rate of graded pulmonary exacerbations, expressed as events per year, with a 52-week timeframe. The endpoint population is described as randomized and treated, which the record says was referred to as the ITT population in this trial. The registry record does not explain how that label was operationalized or how participants with missing follow-up were handled.
The listed secondary outcomes include St. Georges Respiratory Questionnaire total score, antibiotic use prescribed for treated pulmonary exacerbations, time to first graded exacerbation, duration of graded exacerbations, sputum volume, daytime sleepiness scores, and changes in FEV1 and FVC. The record lists 19 outcome measures and 9 analyses, but does not provide the full outcome-by-outcome analysis specifications in the registry record for this discussion. Allocation concealment, recruitment details, formal sample-size justification, and the statistical analysis plan are not reported in the registry record.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: Prior to randomisation, subjects underwent a Mannitol Tolerance Test (MTT) - only those who passed the MTT were eligible to be randomised. 581 patients in total underwent the MTT
Randomisation to First Dose
| Stage | Mannitol | Control |
|---|---|---|
| STARTED | 244 | 241 |
| COMPLETED | 233 | 228 |
| NOT COMPLETED | 11 | 13 |
Reasons for not completing this period:
| Reason | Mannitol | Control |
|---|---|---|
| Adverse Event | 1 | 0 |
| Protocol Violation | 1 | 0 |
| Withdrawal by Subject | 3 | 2 |
| Lost to Follow-up | 2 | 0 |
| Death | 1 | 0 |
| Sponsor decision | 0 | 1 |
| Randomised in error | 3 | 10 |
Blinded Treatment Period
| Stage | Mannitol | Control |
|---|---|---|
| STARTED | 233 | 228 |
| COMPLETED | 191 | 189 |
| NOT COMPLETED | 42 | 39 |
Reasons for not completing this period:
| Reason | Mannitol | Control |
|---|---|---|
| Adverse Event | 16 | 10 |
| Protocol Violation | 1 | 1 |
| Withdrawal by Subject | 17 | 19 |
| Lost to Follow-up | 3 | 2 |
| Death | 0 | 2 |
| Physician Decision | 3 | 3 |
| Unable/unwilling to comply w trial reqs | 2 | 2 |
Analysis population for the primary outcome, as defined in the registry: Randomised and Treated (referred to as the ITT population in this trial)
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: Patients randomised and treated with at least one dose of study medication
| Characteristic | Unit | Mannitol | Control | Total |
|---|---|---|---|---|
| Participants analysed | 233 | 228 | 461 | |
| Age, Continuous | years | 59.30 (SD 14.06) | 60.26 (SD 13.02) | 59.77 (SD 13.55) |
| Sex: Female, Male: Female | Participants | 147 | 142 | 289 |
| Sex: Female, Male: Male | Participants | 86 | 86 | 172 |
| Baseline Pulmonary Exacerbation rate | events/year | 3.20 (SD 1.38) | 3.25 (SD 1.40) | 3.22 (SD 1.39) |
| Baseline % of Predicted FEV1: <60% | participants | 101 | 107 | 208 |
| Baseline % of Predicted FEV1: >=60% | participants | 132 | 121 | 253 |
| Extent of Bronchiectasis: Diffuse | participants | 133 | 118 | 251 |
| Extent of Bronchiectasis: Focal | participants | 77 | 73 | 150 |
| Extent of Bronchiectasis: Both (Diffuse and Focal) | participants | 23 | 37 | 60 |
6. Primary Endpoint
The registry lists the primary outcome as Rate of Graded Pulmonary Exacerbations, measured over 52 weeks.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | GPE events per year |
| Endpoint classification | Event-Rate Endpoint |
The primary endpoint is the rate of graded pulmonary exacerbation events per year during 52 weeks. A pulmonary exacerbation was defined as worsening signs and symptoms that required a change in treatment. The grading system used combinations of main and minor signs and symptoms: increased cough, sputum volume, or sputum purulence were main features; upper respiratory tract infection, fever, increased wheezing, increased dyspnea, increased respiratory rate, increased cardiac frequency of >20%, and increased malaise, fatigue, or lethargy were minor features. The record describes Grade I as requiring 3 main signs and symptoms, Grade II as requiring 2 main signs and symptoms, and Grade III as requiring 1 main and one or more minor signs and symptoms.
A rate endpoint counts events in relation to time under observation, rather than simply classifying each participant as having or not having an event. In general, rates can be useful when participants may experience repeated events and when their observed follow-up time varies. They can represent the burden of recurrent exacerbations during treatment, but interpretation depends on how events and follow-up time were counted and how the comparison was analyzed. Those operational and modeling details are not reported in the registry record.
The endpoint definition links an event to a clinical change that led to treatment modification, making the outcome more specific than a symptom change alone. That definition does not itself establish that all events were equally severe or that event ascertainment was identical across groups. The registry record does not report the group-specific event rates or a single comparative estimate for this endpoint.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies the intended primary comparison and defines the outcome, but the registry entries available for interpretation do not include a single comparative primary-outcome result. In particular, no treatment-group rate estimates, between-group effect estimate, confidence interval, or p-value for the primary outcome is reported in the registry record. The outcome is also flagged as having several categories or time points and not being reduced to one comparison. As a result, the record as represented does not support a statement about the direction, size, or statistical precision of a single primary treatment effect.
This is not evidence that the groups had identical results, nor does it establish that one group had a higher event rate. Without an estimate and its uncertainty, readers cannot assess how compatible the posted results are with effects of different sizes. The study's stated hypothesis and background rationale describe why the question was investigated; neither substitutes for the trial's comparative results.
The registry lists 485 enrolled participants, while the adverse-event information separately gives group-specific numbers at risk. These are different pieces of information, and the record does not explain the relationship between them. They should not be used to infer how many participants contributed primary-outcome follow-up, whether anyone was excluded from an analysis, or why different counts appear in different parts of the record.
The primary outcome is a rate of recurrent, graded events over time, not simply the time to a first exacerbation. The record separately lists time to first graded exacerbation as a secondary outcome. These endpoints answer different questions: a recurrent-event rate concerns event frequency over exposure, while a time-to-first analysis concerns how long it takes for the first event. No results for either endpoint are reported in the registry record, so neither can be used to fill the gap in the primary comparison.
General statistical interpretation requires attention to both the estimate and its uncertainty. A confidence interval, when reported, describes a range of effect values compatible with the data and analysis under the method's assumptions. A p-value, when reported, summarizes how unusual the data would be under a specified null model; it does not measure the probability that a treatment works. Neither type of statistic is available for the primary comparison in this record. Consequently, no conclusion about statistical significance or the practical size of a primary effect can be drawn from the endpoint definition alone.
The record's list of 19 outcome measures and 9 analyses also signals that the primary outcome is part of a wider set of reported measures. Without the analysis plan and complete results, it is not possible to determine which analyses were prespecified, how related outcomes were handled, or whether any adjustment for multiple testing was used. These omissions limit interpretation; they do not establish that an inappropriate analysis occurred.
9. Statistical Methods Explained
What does an event rate represent?
The primary outcome is described as the number of all graded pulmonary exacerbation events observed in one treatment year, with units of GPE events per year. A rate places event counts in the context of time under observation. In general, that can be useful when participants can experience repeated exacerbations or contribute different amounts of follow-up. It differs from a proportion, which would count participants with an event without expressing how long they were observed or how many events each experienced.
For a rate comparison, the analysis needs a defined event count and an exposure-time denominator. The record defines a graded event and states the rate unit, but it does not describe how partial follow-up, recurrent events, or periods without observation were handled. The registry record also does not identify the specific statistical model used for the primary analysis.
Why can rate data require special care?
General statistical explanation: a simple count model may assume that the variation in event counts is adequately described by the mean. In clinical event-rate data, participants may differ in underlying risk, and event counts may vary more than that assumption allows. This is called over-dispersion. If it is present and not accounted for, uncertainty estimates can be too narrow. Analysts may use methods that allow extra variation, or models that account for participant-level clustering or follow-up time, depending on the design and data. The registry record does not report whether over-dispersion was assessed or what model was used, so no such method should be attributed to this trial.
Another general issue is whether events within a participant are statistically related. Repeated exacerbations from the same participant are not necessarily independent observations. Analyses of recurrent events may need to account for that dependence. The endpoint definition says the rate includes all GPE events observed in one treatment year, but the record does not explain how within-participant recurrence was modeled.
What is the role of the endpoint definition?
The event definition determines what is counted. Here, a qualifying exacerbation was a worsening in signs and symptoms requiring a treatment change, with grades based on combinations of main and minor features. This makes the endpoint dependent on symptom assessment and a treatment decision. The registry record gives the grading criteria but does not report whether an adjudication committee reviewed events, whether assessors used additional guidance, or how disagreements were resolved. Those procedures should not be assumed.
Because the event is graded, results could potentially be presented by grade or across categories. The registry record indicates that the primary outcome has several categories or time points and was not reduced to one comparison. Without the corresponding results and analysis specification, the reader cannot determine what comparisons were made or which one was intended to represent the primary inference.
How should uncertainty be read?
General statistical explanation: an effect estimate gives the direction and size of a comparison according to a chosen scale, while an uncertainty interval shows how imprecise that estimate is under the analysis assumptions. For rates, the comparison might be expressed on an absolute or relative scale, but the scale must be stated because the interpretations differ. The primary outcome's unit is reported, but a comparative effect estimate and uncertainty interval are not reported in the registry record.
A confidence interval is not a guarantee that the true value lies within its endpoints, nor does an interval by itself establish clinical importance. Its width reflects precision, which can be affected by the number of observed events, the amount of follow-up, and variability. No confidence interval is included in the primary-outcome details, so the precision of the treatment comparison cannot be assessed.
A p-value is also not a measure of effect size. In general, it describes how inconsistent the observed data are with a specified null hypothesis under the model. It does not indicate the probability that the null hypothesis is true, or that the intervention is effective. The registry record does not report a primary-outcome p-value in the registry record for this explanation.
What do planning illustrations mean?
General statistical explanation: sample-size planning calculations describe the number of participants or events that would be needed under particular assumptions to detect a chosen effect with a selected error rate and power. They are planning illustrations, not observed trial outcomes and not a substitute for the reported effect estimate. The record describes an illustration based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation; it also notes that the effect to detect is a stated fraction of the observed effect. Time-to-event planning is described in terms of total events, while other planning calculations are described as participants per arm.
The planning assumptions do not establish the trial's original design rationale. A formal sample-size justification, including the effect assumed when the study was designed, is not reported in the registry record. The planning figures themselves are not reported in the registry record. Any such illustration must remain distinct from the number enrolled and from observed power, which is not an appropriate retrospective summary of whether an effect was detected.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 19 outcome measures and 9 analyses, including a primary exacerbation-rate outcome and secondary measures of quality of life, antibiotic use, time to first exacerbation, exacerbation duration, sputum volume, daytime sleepiness, and lung function. Considering multiple outcomes can create multiple opportunities for apparently notable findings. General statistical practice may address this through a prespecified hierarchy, adjustment procedures, or clear separation of confirmatory and exploratory analyses. The registry record does not report whether any such strategy was used, so the risk of multiplicity cannot be quantified from these registry entries.
The primary outcome is flagged as having several categories or time points and not being reduced to one comparison. This makes it especially important to know which time point, category, and contrast were prespecified as primary. Those details, along with any multiplicity adjustment, are not reported in the registry record. The absence of that information does not show that no plan existed; it means the plan cannot be evaluated from this record.
The primary analysis population is described as randomized and treated, and called the ITT population in the trial. The record does not clarify whether participants were analyzed according to their randomized assignment regardless of treatment received, how many contributed outcome data, or whether the analysis included all randomized participants. The registry record also does not describe missing-data patterns, imputation, censoring, sensitivity analyses, or handling of withdrawals. Those omissions matter because incomplete follow-up can affect event counts and exposure time, and assumptions about missing information can affect estimates and uncertainty.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Mannitol | 43 | 233 | 18.5% |
| Control | 51 | 228 | 22.4% |
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 |
|---|---|
| Mannitol | 215 of 233 |
| Control | 214 of 228 |
Most frequent serious adverse event terms
| Event term | Organ system | Mannitol | Control |
|---|---|---|---|
| Condition Aggravated | General disorders | 21 of 233 | 26 of 228 |
| Pneumonia | Infections and infestations | 7 of 233 | 7 of 228 |
| Lobar pneumonia | Infections and infestations | 1 of 233 | 2 of 228 |
| Abdominal Pain | Gastrointestinal disorders | 0 of 233 | 2 of 228 |
| Inguinal hernia | Gastrointestinal disorders | 1 of 233 | 1 of 228 |
| Chest pain | General disorders | 2 of 233 | 0 of 228 |
| Skin lacreation | Injury, poisoning and procedural complications | 2 of 233 | 0 of 228 |
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | 1 of 233 | 1 of 228 |
| Anaemia | Blood and lymphatic system disorders | 0 of 233 | 1 of 228 |
| Angina Pectoris | Cardiac disorders | 1 of 233 | 0 of 228 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Mannitol | Control |
|---|---|---|---|
| Condition aggravated | General disorders | 149 of 233 | 159 of 228 |
| Nasopharyngitis | Infections and infestations | 36 of 233 | 30 of 228 |
| Bacteia sputum identified | Investigations | 30 of 233 | 30 of 228 |
| Headache | Nervous system disorders | 27 of 233 | 32 of 228 |
| Cough | Respiratory, thoracic and mediastinal disorders | 30 of 233 | 22 of 228 |
| Haemoptysis | Respiratory, thoracic and mediastinal disorders | 24 of 233 | 23 of 228 |
| Lower respiratory tract infection | Infections and infestations | 16 of 233 | 21 of 228 |
| Diarrhoea | Gastrointestinal disorders | 15 of 233 | 21 of 228 |
| Dsypnoea | Respiratory, thoracic and mediastinal disorders | 20 of 233 | 16 of 228 |
| Nausea | Gastrointestinal disorders | 14 of 233 | 18 of 228 |
Serious events with the highest arm-level rate: condition aggravated (11.4%), pneumonia (3.1%), abdominal pain (0.9%), lobar pneumonia (0.9%), chest pain (0.9%).
The serious adverse-event figures list 233 participants at risk in the mannitol group, with 43 affected, and 228 at risk in the control group, with 51 affected. These are counts of participants affected as recorded for the serious adverse-event grouping; they are not a direct comparison of event rates unless the relevant definitions, observation periods, and analysis are also considered. The registry record does not provide a comparative estimate or uncertainty interval for these figures.
For other adverse events, the record lists 215 affected among 233 at risk in the mannitol group and 214 affected among 228 at risk in the control group. The serious and other adverse-event groupings are distinct fields in the record. The counts should not be added together or interpreted as mutually exclusive categories; the record does not explain overlap or provide further event-level detail.
The leading serious-event terms listed are Condition Aggravated at 11.4%, Pneumonia at 3.1%, Abdominal Pain at 0.9%, Lobar pneumonia at 0.9%, Chest pain at 0.9%, and Skin lacreation at 0.9%. These percentages are presented without arm-specific denominators or further detail about whether they refer to participants, events, or another reporting basis. They therefore should not be used to infer comparative risks for individual terms. Death counts are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The trial record describes a randomized comparison of inhaled mannitol 400mg with matched control containing inhaled mannitol 50mg, and defines graded pulmonary exacerbation rate as the primary outcome over 52 weeks. It also provides the clinical criteria used to identify and grade an exacerbation. These details establish what the study set out to compare and how the principal outcome was intended to be understood.
They do not establish what the comparison found. A single comparative primary-outcome result, including group rates, an effect estimate, and its uncertainty, is not reported in the registry record. Accordingly, the record as represented in the registry record cannot show whether the event rate was higher or lower in either group, how large a difference might have been, or how precisely it was estimated. A missing result is not evidence of no difference.
The background statement describes the investigators' rationale and hypothesis about mucus clearance, symptoms, and lung health. Such statements explain the research question but are not outcome findings. Likewise, the list of secondary outcomes does not establish a change in quality of life, antibiotic use, lung function, or any other secondary measure; results for those measures are not reported in the registry record used.
The safety counts describe participants affected in the registry's adverse-event groupings, but do not by themselves establish that one regimen is safer. The record does not provide comparative safety estimates, uncertainty intervals, exposure-adjusted analyses, or death counts. The listed serious-event terms also lack the detail needed for an arm-by-arm comparison.
Overall, the available record supports a description of the design, comparator, endpoint definition, listed outcomes, and reported adverse-event counts. It does not support a conclusion about treatment benefit or lack of benefit, nor a definitive comparative safety conclusion. Such interpretations require the trial's outcome estimates and the methods used to derive them.
13. Why This Trial Matters Statistically
This study is statistically notable for using a recurrent-event rate as its primary endpoint. A rate can capture multiple exacerbations per participant over follow-up, unlike an outcome that records only whether a participant experienced at least one event. That makes the endpoint relevant to event burden, while also making the analysis dependent on event ascertainment, follow-up time, and the treatment of repeated events.
The grading definition is another important feature. Events were tied to worsening symptoms that required a treatment change, and the criteria distinguished grades through combinations of main and minor signs and symptoms. Such a definition helps specify what qualifies as an outcome, but interpretation also depends on consistent assessment across groups. The registry record does not describe event adjudication or the statistical handling of repeated events.
The comparison is also specific: inhaled mannitol 400mg versus matched control containing inhaled mannitol 50mg. That is not the same question as comparing treatment with no mannitol. Recognizing the comparator is necessary to interpret any eventual contrast accurately.
Finally, the registry record illustrates why a detailed endpoint description is not enough to evaluate trial findings. The primary outcome's event-rate unit and definition are available, but a single comparative result and its uncertainty are not. Without those, readers cannot judge the estimated effect or its precision. The listed 19 outcome measures and 9 analyses also make transparent reporting of the analysis plan and multiplicity approach important, neither of which is reported in the registry record.
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 central limitation for interpretation is that the registry record does not report a single comparative result for the primary endpoint. The record flags the outcome as having several categories or time points and not being reduced to one comparison. Without group-specific rates, an effect estimate, or uncertainty, the primary treatment contrast cannot be evaluated.
Several statistical details are also not reported in the registry record: the primary analysis model, how exposure time and recurrent events were handled, whether over-dispersion was assessed, and how missing observations or withdrawals were treated. The analysis population is called randomized and treated and referred to as ITT, but the record does not explain the operational definition or how it relates to the randomized allocation.
The record lists 19 outcome measures and 9 analyses but does not describe a multiplicity strategy, a hierarchy among outcomes, or the complete prespecified analysis plan. It does not provide the original sample-size justification or enough detail to assess whether the study's planning assumptions matched the eventual analysis. Planning illustrations described in the record are not themselves trial results.
For safety, participant counts are listed for serious and other adverse events, but comparative estimates and uncertainty are not reported. The basis for the listed serious-event percentages is not further specified, and death counts are not reported in the registry record. These limitations constrain interpretation; they do not establish that the trial methods were inadequate or that unreported results were unfavorable.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis — NCT00669331.
- Registry record last updated 2016-04-29; status last verified 2016-03.
- Results first posted 2016-04-29.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
NCT00669331 is a completed Phase III randomized, parallel-group trial of inhaled mannitol for bronchiectasis, with 485 participants recorded as enrolled. The intervention was inhaled mannitol 400mg; the matched control was inhaled mannitol 50mg. The study used quadruple masking and examined treatment over 52 weeks.
The primary outcome was the rate of graded pulmonary exacerbations per year. The registry defines qualifying exacerbations as worsening signs and symptoms requiring a treatment change and describes the grading criteria. Secondary outcomes included quality of life, antibiotic use, exacerbation timing and duration, sputum volume, daytime sleepiness, and lung function.
A single comparative primary-outcome result is not reported in the registry record. The record also does not report the primary analysis model, missing-data methods, or multiplicity approach. Serious adverse-event counts are listed by group, but comparative safety estimates and death counts are not reported.