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 A Safety Study of Liposomal Cyclosporine A to Treat Bronchiolitis After Hematopoietic Transplant (BOSTON-4) (NCT04107675), a randomized phase 2 study. The primary outcome is Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04107675 |
| Phase | Phase 2 |
| Condition | Bronchiolitis Obliterans Syndrome (BOS), GVHD, Chronic, Stem Cell Transplant Complications |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Single |
| Enrollment | 6 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Zambon SpA |
| Results posted | Yes |
2. Clinical Question
Population
Adults with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation were the intended study population. The primary safety analysis set was defined as randomized patients who had received at least a partial dose of the investigational medicinal product. The registry record does not report further eligibility details or the number meeting that analysis-set definition.
Intervention
The study compared aerosolized liposomal cyclosporine A at 10 mg or 5 mg, each given with standard-of-care therapy. Both regimens were described as twice daily for up to 12 weeks.
Comparator
The comparator was inhaled liposomal placebo alongside standard-of-care therapy, also described as twice daily for up to 12 weeks. The study was randomized and single-blind; which parties were masked is not reported in the registry record.
Primary question
The primary objective was to assess tolerability and safety of the two liposomal cyclosporine A dose levels compared with placebo, all added to standard care. The primary endpoint counted specified local tolerability events from baseline to Visit 3 at Week 4. The registry record does not report a numerical primary endpoint result or an analysis comparing the groups.
3. Trial Design
This was a randomized, single-blind, parallel-group Phase IIa study sponsored by Zambon SpA. Its official title describes a multicenter safety study of liposomal cyclosporine A for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. The registry lists an enrollment of 6 and a status of terminated. The study started on 2020-02-11, and its primary completion date is listed as 2022-06-16. The reason for termination is not reported in the registry record.
The study compared aerosolized liposomal cyclosporine A at 10 mg and 5 mg with liposomal placebo. Standard-of-care therapy was included in the description of each group. Each inhaled regimen was described as twice daily for up to 12 weeks. The record identifies a single-blind design but does not say who was masked or how masking was maintained. It also does not report the number of participating centers or details of randomization and allocation concealment.
The primary objective concerned safety and tolerability. Secondary objectives concerned pharmacokinetics, exploratory efficacy, and quality of life. The listed secondary outcomes include local tolerability events, adverse events and serious adverse events by severity during the first 12 weeks of treatment, and whole-blood cyclosporine A concentrations and trough levels. The registry record lists five outcome measures but no analyses. It does not report the protocol’s planned sample-size justification, statistical analysis plan, or reason for ending the study.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Overall Study
| Stage | L-CsA 10 mg Plus Standard of Care | L-CsA 5 mg Plus Standard of Care | Liposomal Placebo Plus Standard of Care |
|---|---|---|---|
| STARTED | 2 | 2 | 2 |
| COMPLETED | 2 | 2 | 2 |
| NOT COMPLETED | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: The Safety Analysis Set (SAF) was defined as all randomized patients who had received a partial dose of IMP at least once.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
Population: The Safety Analysis Set (SAF) was defined as all randomized patients who had received a partial dose of IMP at least once.
| Characteristic | Unit | L-CsA 10 mg Plus Standard of Care | L-CsA 5 mg Plus Standard of Care | Liposomal Placebo Plus Standard of Care | Total |
|---|---|---|---|---|---|
| Participants analysed | 2 | 2 | 2 | 6 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 2 | 2 | 2 | 6 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 | 0 |
| Age, Continuous | years | 55.5 (SD 0.71) | 63.0 (SD 0.00) | 46.0 (SD 12.73) | 54.8 (SD 9.52) |
| Sex: Female, Male: Female | Participants | 0 | 2 | 1 | 3 |
| Sex: Female, Male: Male | Participants | 2 | 0 | 1 | 3 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 1 | 1 | 2 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 0 | 0 | 1 | 1 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 2 | 1 | 0 | 3 |
| Region of Enrollment: France | participants | 1 | 1 | 0 | 2 |
| Region of Enrollment: Germany | participants | 1 | 0 | 1 | 2 |
| Region of Enrollment: Spain | participants | 0 | 1 | 1 | 2 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Local Tolerability Events of Interest From Baseline to Visit 3 (Week 4), measured over at Week 4 (visit 3).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | number of local events |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the number of local tolerability events of interest from baseline to Visit 3 at Week 4. The record identifies cough, wheezing, bronchospasm, throat irritation, and change from baseline in FEV1 to Visit 3 as events considered for this endpoint. The listed unit is number of local events.
Counting local events is a way to describe tolerability during treatment, rather than to estimate a single clinical efficacy effect. For an inhaled intervention, recording symptoms such as cough or wheezing can capture experiences occurring around administration, while the inclusion of change in FEV1 adds a lung-function measure to the endpoint definition. This is a general explanation of the types of information such an endpoint can convey; it does not establish how the registry combined or classified the listed components.
The registry record does not report the observed event counts, the way repeated events were handled, or a numerical comparison between treatment groups. It therefore does not establish the frequency of these events in any group or the precision of a group contrast. The safety analysis set was defined as randomized patients who received a partial dose of the investigational medicinal product at least once; the number included in that set is not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes a small randomized safety study with six enrolled participants and three named regimens: liposomal cyclosporine A 10 mg plus standard of care, liposomal cyclosporine A 5 mg plus standard of care, and liposomal placebo plus standard of care. The record lists no analyses. In particular, it does not report numerical results for the primary local-tolerability endpoint or an estimated contrast between groups. Without those results, the primary safety question cannot be answered from the registry record.
The adverse-event figures describe affected participants in the groups. For serious adverse events, 1 participant in the 10 mg group was affected, while 0 participants in the 5 mg group and 0 in the placebo group were affected. Each group lists 2 participants at risk. For other adverse events, the record lists 2 affected participants in the 10 mg group, 1 in the 5 mg group, and 1 in the placebo group; each group again lists 2 at risk. No deaths are listed in any group. These counts are descriptive. They do not show whether an event was caused by treatment, and the small group sizes make the observations highly limited as a basis for comparing event patterns.
The most common serious-event term listed is moderate acute respiratory failure at 50.0%. The record does not specify a denominator alongside that percentage in the registry record for this analysis, so it should not be interpreted as a group-specific risk or as a comparison among groups. The adverse-event summary also does not provide event timing, recurrence, exposure-adjusted rates, or detailed clinical context.
A randomized design is intended to support comparisons by reducing systematic differences between assigned groups, but randomization does not make a comparison precise when few participants are enrolled. No confidence intervals, p-values, effect estimates, or inferential analyses are reported. The registry record therefore supports a description of the listed counts and design, not a conclusion about comparative safety or efficacy. The reason for termination and the implications of termination for follow-up or data completeness are also not reported.
9. Statistical Methods Explained
Statistical methods help distinguish what an observed count can describe from what a study can estimate. In this record, the primary endpoint is a count of local tolerability events through Week 4, but no numerical endpoint results or statistical analyses are listed. The following explanations are general; they do not describe an analysis plan confirmed by the registry record.
What does randomization contribute?
In general, randomization assigns participants to groups using a chance-based process. It is intended to make measured and unmeasured participant characteristics less systematically different across groups at the point of assignment. This supports interpretation of between-group contrasts, but it does not guarantee balance in a small study. The registry identifies the trial as randomized, while the sequence-generation method, allocation concealment, and any stratification are not reported in the registry record.
Allocation concealment and masking address different concerns. Concealment protects the assignment process before a participant enters a group; masking can reduce differences in care or assessment after assignment. The record describes the study as single-blind but does not identify who was masked or report how masking was maintained. Because the primary endpoint includes symptoms and tolerability events, knowledge of treatment assignment could matter to how events are noticed or reported. That is a general measurement consideration, not evidence that masking failed.
How should an event count be understood?
A count endpoint records the number of events, rather than only whether a participant experienced at least one event. Counts can differ because of the number of participants observed, the amount of time they were observed, and the frequency of repeated events. For a group comparison, the analysis method should reflect the endpoint’s distribution and the observation period. The registry does not report whether the primary analysis counted events per participant, how repeated episodes were defined, or how observation time was handled.
In general, count data may show over-dispersion: the variability can be greater than expected under a simple Poisson model. If over-dispersion is present, a model that assumes Poisson variability can produce standard errors that are too small and confidence intervals that are too narrow. Alternative count models or robust methods may be considered, depending on the data and analysis plan. The registry record does not report a model, a dispersion assessment, or an analysis of the primary count endpoint, so no particular method can be attributed to this trial.
What would an estimate and confidence interval add?
In general, an effect estimate summarizes the size and direction of a group contrast, while a confidence interval describes the statistical uncertainty around that estimate under the analysis assumptions. A narrow interval indicates greater precision than a wide interval; neither an estimate nor its interval, by itself, establishes clinical importance. The registry record lists no primary endpoint estimate or confidence interval. The adverse-event counts are not accompanied by inferential comparisons or intervals, so the precision of the apparent group differences cannot be assessed from the record.
What can be inferred from the safety counts?
General safety summaries may distinguish participants with at least one event from total events, and may separately report serious events, severity, and event terms. A participant count avoids treating multiple events in the same participant as independent participants, but it does not convey how many total episodes occurred. Here, the registry lists affected and at-risk participant counts for serious and other adverse events. The record does not report exposure-adjusted rates, event-level counts, or a causal assessment. With few participants, a count of zero is not evidence that an event cannot occur, and counts across groups do not by themselves establish a treatment-related difference.
What does a planning calculation mean?
In general, sample-size planning uses assumptions about an effect, variability, allocation, and a target error rate to illustrate the number of participants that may be needed for a planned comparison. Such an illustration is distinct from observed power, which should not be inferred from the study’s observed results. The registry record does not report the trial’s own sample-size justification or a complete prespecified analysis plan. Any planning illustrations associated with the posted material are not observed trial outcomes and do not replace the missing primary endpoint analysis.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists a primary endpoint and several secondary objectives, including pharmacokinetics, exploratory efficacy, and quality of life. It also lists secondary outcome measures relating to local tolerability, adverse events and serious adverse events, and whole-blood cyclosporine A concentrations and trough levels. When a study evaluates multiple outcomes, time points, dose groups, or comparisons, the chance of finding at least one apparently unusual result can increase. General approaches to this issue include prespecifying a hierarchy or adjusting the interpretation of multiple tests. The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or which comparisons were intended for formal testing.
The record lists no analyses. It does not report a statistical analysis plan specifying models, covariate adjustment, hypothesis tests, confidence intervals, or rules for selecting analyses. No primary endpoint result is listed, so no confirmatory interpretation or adjustment for multiple testing can be evaluated from the record.
Missing-data methods are not reported in the registry record. It does not specify how missed visits, incomplete endpoint assessments, withdrawal, or missing safety follow-up were handled. The number of participants included in the defined Safety Analysis Set is also not reported. That set includes randomized patients who received a partial dose at least once, but the record does not provide participant flow or explain whether every enrolled participant met the definition.
The six enrolled participants and the group-level safety counts should therefore be read alongside this lack of information about analysis populations and completeness. The registry does not establish whether outcomes were available for all enrolled participants or whether missing observations could have affected the summaries.
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 |
|---|---|---|---|
| L-CsA 10 mg Plus Standard of Care | 1 | 2 | 50.0% |
| L-CsA 5 mg Plus Standard of Care | 0 | 2 | 0.0% |
| Liposomal Placebo Plus Standard of Care | 0 | 2 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| L-CsA 10 mg Plus Standard of Care | 0 of 2 |
| L-CsA 5 mg Plus Standard of Care | 0 of 2 |
| Liposomal Placebo Plus Standard of Care | 0 of 2 |
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 |
|---|---|
| L-CsA 10 mg Plus Standard of Care | 2 of 2 |
| L-CsA 5 mg Plus Standard of Care | 1 of 2 |
| Liposomal Placebo Plus Standard of Care | 1 of 2 |
Most frequent serious adverse event terms
| Event term | Organ system | L-CsA 10 mg Plus Standard of Care | L-CsA 5 mg Plus Standard of Care | Liposomal Placebo Plus Standard of Care |
|---|---|---|---|---|
| moderate acute respiratory failure | Respiratory, thoracic and mediastinal disorders | 1 of 2 | 0 of 2 | 0 of 2 |
Most frequent non-serious adverse event terms
| Event term | Organ system | L-CsA 10 mg Plus Standard of Care | L-CsA 5 mg Plus Standard of Care | Liposomal Placebo Plus Standard of Care |
|---|---|---|---|---|
| Throat irritation | Respiratory, thoracic and mediastinal disorders | 1 of 2 | 1 of 2 | 1 of 2 |
| Cough | Respiratory, thoracic and mediastinal disorders | 0 of 2 | 1 of 2 | 1 of 2 |
| Productive cough | Respiratory, thoracic and mediastinal disorders | 0 of 2 | 1 of 2 | 0 of 2 |
| Wheezing | Respiratory, thoracic and mediastinal disorders | 1 of 2 | 0 of 2 | 0 of 2 |
| Muscle spasms | Musculoskeletal and connective tissue disorders | 1 of 2 | 0 of 2 | 0 of 2 |
Serious events with the highest arm-level rate: moderate acute respiratory failure (50.0%).
The serious adverse-event summary lists 2 participants at risk in each group. It records 1 affected participant in the liposomal cyclosporine A 10 mg plus standard-of-care group, and 0 affected participants in both the 5 mg group and the liposomal placebo group. The record lists 0 deaths in each group. For other adverse events, it lists 2 affected participants in the 10 mg group and 1 in each of the other groups. These are participant counts, not a comparison adjusted for treatment exposure.
The most common serious-event term is reported as moderate acute respiratory failure, with 50.0% listed. The denominator and group attribution for this percentage are not reported in the registry record, so that figure should not be treated as a rate for a particular group. A serious adverse event is a safety classification; the listing alone does not establish that the study treatment caused the event. The record does not provide event-level details, timing, duration, relatedness assessments, or a statistical comparison. With only the listed counts, the figures describe what was recorded but do not provide a precise estimate of comparative risk.
12. What the Result Does, and Does Not, Mean
The registry record establishes that a randomized, single-blind Phase IIa safety study was conducted to compare two doses of aerosolized liposomal cyclosporine A with liposomal placebo, each alongside standard-of-care therapy, in adults with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. It also gives the stated primary endpoint, selected secondary outcomes, enrollment, study status, and adverse-event counts.
It does not provide the primary endpoint event counts or an analysis comparing the groups. It therefore cannot show from the registry record whether local tolerability events differed across regimens, how large any difference might have been, or how precisely a difference was estimated. The listed adverse-event counts can be described, but they are not a causal assessment and are not accompanied by uncertainty intervals or a formal comparison. The 50.0% serious-event term is not interpretable as a group-specific rate without a reported denominator and attribution.
The record also does not explain why the study was terminated, how missing observations were handled, or whether the posted safety counts represent complete follow-up. These omissions limit interpretation of the observed counts. The absence of reported deaths or serious events in some groups does not establish that such events are impossible, and the presence of an event in a group does not establish that the intervention caused it.
Accordingly, the information supports a description of the trial’s design and recorded safety summaries, but not a conclusion that one regimen is safer, more tolerable, or more effective than another. The registry record does not report a primary efficacy result, and the study’s exploratory objectives should not be treated as established findings in the absence of reported analyses.
13. Why This Trial Matters Statistically
This study is statistically notable because it addresses a safety and tolerability question using a randomized comparison of two aerosolized liposomal cyclosporine A dose levels with placebo, while standard-of-care therapy was included in each group. A randomized design can make between-group assessment more informative than an uncontrolled description, provided the study reports the results and the analysis is appropriate to the outcome.
Here, the registry lists 6 enrolled participants and no analyses. The primary endpoint is a count of local tolerability events through Week 4, but numerical results for that endpoint are not reported. The safety summary contains affected-participant counts, yet those counts cannot substitute for a reported endpoint analysis, a comparison estimate, or a measure of uncertainty. This illustrates a central statistical distinction: having an outcome defined in a registry is not the same as having a result that can be evaluated.
Small group sizes also make descriptive safety data difficult to generalize. Counts can identify what was recorded among participants in the study, but they give limited information about the range of plausible event frequencies beyond those participants. Without intervals, exposure information, and fuller follow-up details, apparent differences in counts should not be treated as precise estimates.
The record further demonstrates why transparency about termination, analysis populations, missing data, and multiplicity matters. Those details help readers understand which observations contributed to each outcome and how the comparisons were intended to be interpreted. Their absence does not reveal what happened in the study, but it restricts what can be concluded from the posted information.
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.
Several trial-specific details needed to assess the results are not reported in the registry record. The reason for termination is not given, and the record does not state whether termination affected recruitment, treatment exposure, follow-up, or endpoint availability. Although enrollment is listed as 6, participant flow across screening, randomization, treatment, and analysis is not described. The number included in the Safety Analysis Set is not reported.
The primary endpoint definition lists local symptoms and change from baseline in FEV1 to Visit 3, but the record does not explain the rules used to count events, whether repeated events were counted separately, or how the components were combined. Numerical endpoint results, group comparisons, and precision estimates are not reported. The absence of those results prevents assessment of the primary safety and tolerability objective.
The safety summary is limited to affected-participant counts and the listed serious-event term. Event timing, duration, severity details beyond the listed term, treatment relatedness, total event counts, and exposure-adjusted rates are not reported. The denominator and group attribution for the 50.0% serious-event term are also not reported in the registry record.
Further limitations include unreported details of masking, randomization procedures, the statistical analysis plan, missing-data handling, and multiplicity. The record identifies secondary pharmacokinetic and exploratory objectives but lists no analyses. These limitations are specific to the information available in the registry record; they do not establish that the underlying study documents lacked these details.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Safety Study of Liposomal Cyclosporine A to Treat Bronchiolitis After Hematopoietic Transplant (BOSTON-4) — NCT04107675.
- Registry record last updated 2023-10-03; status last verified 2023-09.
- Results first posted 2023-10-03.
- 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
NCT04107675 is a randomized, single-blind, parallel-group Phase IIa safety study of aerosolized liposomal cyclosporine A for bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. It compared 10 mg and 5 mg liposomal cyclosporine A with liposomal placebo, alongside standard-of-care therapy. Enrollment was 6, the study status is terminated, and the primary completion date is listed as 2022-06-16.
The primary endpoint counted local tolerability events through Visit 3 at Week 4. The registry lists adverse-event counts but no primary endpoint analyses. The reason for termination, the primary endpoint results, and the statistical analysis plan are not reported in the registry record.