Targeted Therapy of Bronchiolitis Obliterans Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Targeted Therapy of Bronchiolitis Obliterans Syndrome (NCT01307462), a na phase 2 study. The primary outcome is Number of Subjects Who Failed Treatment.

2. Clinical Question

3. Trial Design

This completed phase II trial evaluated a three-drug regimen in patients with bronchiolitis obliterans following stem cell transplant. The record lists an enrollment of 36. It describes one treatment group, rather than a randomized comparison: allocation is listed as NA, and the study model is single group. Masking is listed as NONE, so the record does not describe blinded treatment assignment or outcome assessment.

Participants in the treatment group received fluticasone propionate, azithromycin, and montelukast sodium. The regimen description specifies fluticasone propionate inhaled PO BID, azithromycin PO 3 days a week, and montelukast sodium PO QD. Treatment was to continue for 6 months unless disease progression or unacceptable toxicity occurred. The registry record does not report whether participants followed this schedule or how treatment exposure varied.

The primary endpoint was treatment failure within 3 months after study medication initiation, defined using a sustained decrease in FEV1 from baseline and confirmation on a second pulmonary function test. Secondary outcomes included serious adverse events attributed to FAM, treatment discontinuation related to those events, lung function measures, blood molecular markers, other chronic GVHD characteristics, steroid exposure, and patient-reported symptoms. The record lists the study as completed, with a start of 2011-06 and primary completion of 2014-09. Completion status does not itself indicate the direction or size of the findings.

Because there is no concurrent control group, changes observed during treatment cannot be separated from changes that might have occurred over time or under other care. The design can describe outcomes among participants in the treated group, but it does not support a direct randomized estimate of FAM versus a comparator.

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

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects Who Failed Treatment, measured over Within 3 months after initiation of study medications.

The primary endpoint counts participants who met the registry definition of treatment failure within 3 months after initiating the study medications. Failure was defined as a sustained, absolute decrease in FEV1 of 10% predicted or more relative to baseline. The decrease had to be confirmed by a second pulmonary function test 2 weeks after the first measurement.

FEV1 is a pulmonary function measure. In general, a change-based endpoint can capture worsening relative to a participant’s own baseline, while requiring confirmation can help distinguish a persistent change from a single measurement. Here, the confirmation rule is part of the endpoint definition; a single qualifying test alone would not meet the stated definition.

The registry specifies a count of participants, not a mean change in FEV1 or a time-to-event estimate. The primary result—the number who met the failure definition—is not reported in the registry record. The record also does not report the participant-level measurements or analysis details needed to evaluate how the endpoint was applied in practice.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a participant count: the number meeting a prespecified treatment-failure definition during the stated follow-up window. The definition combines a threshold for change in FEV1, a requirement that the decrease be sustained, and confirmation on a subsequent pulmonary function test. Each element matters. A threshold makes the event definition explicit, while confirmation is intended to distinguish a persistent change from an isolated measurement. The registry record gives these criteria but does not report the count that resulted from applying them.

What does a count endpoint tell us?

A count of participants with an event describes how many people in the study group experienced the defined outcome. It is not, by itself, a treatment effect. In a single-group study, the count has no concurrent randomized control outcome against which to estimate a treatment contrast. A count can be useful for describing what occurred in the enrolled group, but interpretation depends on the population, follow-up, event definition, and completeness of outcome assessment.

The registry identifies the endpoint unit as participants and gives the timeframe as within 3 months after study medications began. This time window is important: an event after that window would not be part of the endpoint as defined, even if it were clinically relevant. The record does not report how many participants had complete pulmonary function testing, how missing measurements were handled, or whether the endpoint was analyzed in a particular population.

Why does a confidence interval matter?

In general, a confidence interval communicates the uncertainty around an estimate. For a participant count or event proportion, it can indicate how much uncertainty remains because the study includes a limited group of participants. A narrow interval would indicate greater statistical precision than a wide interval, but precision does not resolve limitations in design, outcome measurement, or applicability. The registry record does not report a confidence interval for the primary endpoint, and the observed primary result is also not reported.

A p-value, in general, assesses how compatible the observed data are with a specified statistical null model under the assumptions of the analysis. It does not measure the size or clinical importance of an effect, and it does not prove that a treatment caused an outcome. No primary p-value is reported in the registry record. Because this study is single group, a p-value from a within-group analysis would not create the missing randomized comparison.

How should the planning illustrations be read?

The registry’s sample-size assumptions describe planning illustrations, not the original design of this single-group trial. Those illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect defined as a stated fraction of an observed effect. They are hypothetical planning calculations and are not observed power. The record does not report that the trial itself used a two-arm design or those assumptions to set its enrollment.

In general, a planning calculation estimates the amount of information a future study might need under chosen assumptions. Its result depends on the assumed effect, the statistical model, the significance threshold, and the desired power. If the assumed effect is uncertain or does not match the effect a future study aims to detect, the resulting planning estimate may be a poor guide. The registry record does not report the trial’s own sample-size justification or enough planning details to assess one.

Why can over-dispersion matter?

General statistical context: over-dispersion occurs when observed variation in event counts is greater than a model expects. If a count model assumes less variability than the data contain, its standard errors may be too small and its uncertainty estimates too optimistic. The primary endpoint is described as a participant count, but the registry record does not report a count model, an over-dispersion assessment, or a statistical model for the primary endpoint. No conclusion about whether over-dispersion was relevant to the analysis can therefore be drawn.

The record lists 29 analyses and 10 outcome measures. Without descriptions of the analyses, it is not possible to determine which were primary, exploratory, adjusted, or repeated assessments. The statistical analysis plan, handling of repeated measurements, estimation methods, and any prespecified sensitivity analyses are not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Treatment (BOS Therapy)")
n      <- c(36)
events <- c(2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Treatment (BOS Therapy)  36  2  5.6  0.7  18.7  1.5  18.1  1.7  18.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 10 outcome measures and 29 analyses. Examining multiple outcomes or conducting multiple analyses can increase the chance of finding an apparently notable result by chance. In general, methods such as prespecifying a primary analysis or adjusting for multiple testing can help readers interpret a family of results. The registry record does not report whether such methods were used, how the analyses relate to the outcome measures, or which results were considered confirmatory.

The primary endpoint is defined, but its observed result is not reported. The record also does not report an analysis population for the primary endpoint, a participant flow account, or how missing pulmonary function tests and other missing measurements were handled. It is therefore not possible to assess whether all enrolled participants contributed to each endpoint or whether missingness could have affected the findings.

The statistical analysis plan, interim analyses, and sample-size justification are not reported in the registry record. Their absence from the record should not be read as evidence that a particular procedure was or was not used; it means those methods cannot be evaluated from the registry information. Without analysis details and outcome results, the effect of multiplicity and missing data on the reported findings cannot be determined.

12. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (8.3%), lung infection (8.3%), dyspnea (8.3%), pain (5.6%), hyperglycemia (5.6%).

For the Treatment (BOS Therapy) group, the adverse-event record lists 36 subjects at risk for serious events and 24 subjects affected in that category. It also lists 36 subjects at risk for other events and 9 subjects affected in that category. The record lists 1 death. These are reported counts; they do not establish that the events or death were caused by FAM. The record does not report a causal assessment for the death in the information.

The listed serious-event terms include pneumonia, lung infection, and dyspnea, each reported as 8.3%; pain and hyperglycemia, each at 5.6%; and edema limbs at 2.8%. These percentages are reported as serious-event terms, not as evidence that treatment caused the events. The registry record does not provide further detail about event timing, duration, recurrence, or overlap between terms.

The secondary outcome description refers to grade 3-5 serious adverse events attributable to FAM and subjects who stopped FAM as a result. The adverse-event counts alone do not answer that attribution-specific question. The record does not report the number who stopped FAM because of these events in the information available for interpretation.

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

The registry record establishes that a phase II, single-group study was completed and specifies a primary treatment-failure endpoint. It does not report the observed number of participants who met that endpoint. Without that outcome, readers cannot determine from the record whether the endpoint occurred often or infrequently in the study group, or how precisely its frequency was estimated.

The study’s design also limits what an outcome could establish. With no concurrent comparator, an observed change during treatment would not by itself show that the regimen caused the change. A randomized comparison can help distinguish treatment effects from other influences; this record does not describe one. The single-group findings would therefore be descriptive rather than a direct estimate of FAM versus another approach.

The listed adverse-event counts are relevant to describing events recorded during the study, but they do not establish treatment causality. They also do not provide a complete account of the attribution-specific secondary outcome or treatment discontinuations. The registry record does not report enough information to assess event timing, overlap, or how safety events were analyzed.

Completion status means the study is listed as completed in the registry; it does not indicate that the primary question was answered positively or negatively. The record supports statements about the study population description, regimen, endpoint definition, and posted safety counts. It does not support a conclusion about the primary treatment effect, comparative effectiveness, or the cause of individual adverse events.

14. Why This Trial Matters Statistically

This trial illustrates the distinction between defining an endpoint and reporting its result. The registry gives a precise operational definition for treatment failure: a sustained FEV1 decrease from baseline of 10% predicted or more, confirmed by a second pulmonary function test. That level of definition helps clarify what outcome the study intended to count. However, without the observed count and an uncertainty estimate, readers cannot judge the result’s magnitude or precision.

The design is also central to statistical interpretation. A single-group study can describe outcomes among treated participants, but it does not provide the randomized counterfactual needed for a direct treatment comparison. This limitation does not make descriptive data meaningless; it does constrain the causal claims that can be supported.

The record also lists a range of secondary outcomes and analyses. Multiple outcomes can offer a broader view of lung function, safety, symptoms, and related measures, but they make transparent analysis planning important. The registry record does not report whether multiplicity was addressed or how analyses were selected. These omissions make it harder to distinguish confirmatory findings from exploratory ones.

Finally, the safety record demonstrates why event counts and treatment attribution should be read separately. Reported serious events describe what was recorded in the group; they do not alone establish that the regimen caused those events. Keeping design, endpoint definition, uncertainty, and attribution distinct is essential when interpreting a completed clinical trial.

15. 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 primary limitation for interpretation is that the registry record does not report the observed primary endpoint result. It therefore offers no primary effect estimate or confidence interval with which to judge the frequency or precision of treatment failure. The record also does not report the analysis method used for that endpoint.

The single-group design, allocation listed as NA, and masking listed as NONE mean there is no concurrent randomized comparison described. Any within-group change would be difficult to distinguish from changes over time, other care, measurement variation, or other influences. The record does not describe a blinded outcome assessment.

Additional limitations arise from missing methodological detail. The registry record does not report how missing measurements were handled, which analysis population was used, or whether the statistical analysis plan included multiplicity adjustments or sensitivity analyses. It also does not report the sample-size justification for the trial. Although safety counts and event terms are listed, detail on timing, overlap, and attribution is not reported in the registry record. These gaps limit assessment of both the primary question and the secondary outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Targeted Therapy of Bronchiolitis Obliterans Syndrome — NCT01307462.
• Registry record last updated 2017-10-04; status last verified 2017-09.
• Results first posted 2017-10-04.
• 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.

19. Record Summary

NCT01307462 is a completed phase II, single-group study of fluticasone propionate, azithromycin, and montelukast sodium in patients with bronchiolitis obliterans after stem cell transplant. The registry lists an enrollment of 36 and a treatment period of 6 months unless disease progression or unacceptable toxicity occurred.

The primary endpoint was the number of participants with treatment failure within 3 months, defined by a sustained FEV1 decrease of 10% predicted or more from baseline and confirmation on a second pulmonary function test 2 weeks later. The primary endpoint result is not reported in the registry record. Safety counts and serious-event terms are listed, but they do not establish treatment causality. No randomized comparator is described.