FUTURE 3 Study Extension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for FUTURE 3 Study Extension (NCT01338415), a non-randomized phase 3 study. The primary outcome is Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation.

2. Clinical Question

3. Trial Design

FUTURE 3 Study Extension is described as a prospective, multicenter, open-label extension study and is listed as Phase 3. Its purpose was to evaluate long-term safety, tolerability, and efficacy of the pediatric formulation of bosentan given two versus three times a day in children with pulmonary arterial hypertension. The registry records a parallel model, non-randomized allocation, and no masking. Enrollment is listed as 58.

The two principal arm descriptions concern participants who received 2 mg/kg bosentan twice daily or three times daily during the FUTURE 3 core study and continued the same regimen in the extension. Thus, the groups reflect prior treatment assignment and continued dosing, not a newly randomized comparison. The registry also lists a group titled “Bosentan 2mg/kg b.i.d or t.i.d. During EUTP.” Its relation to the two continued-regimen groups is not explained in the record.

The registry lists study start as 2011-03-08, primary completion as 2014-08-13, and status as completed. It reports an average timeframe of up to 62 weeks for the primary safety outcome. The outcome description says events were presented cumulatively in FUTURE 3 and the extension, and were included through seven days after permanent study-drug discontinuation. Consequently, the posted endpoint is not described as an extension-only count.

Because the study was non-randomized and open-label, the regimen groups should not be read as if they were exchangeable groups formed by random assignment. The registry does not report the allocation process, reasons for choosing or continuing a regimen, or details of any protocol-defined adjustment for differences between groups. Further design details of that kind 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: 64 patients were randomized in the FUTURE 3 core study, among whom 58 were enrolled in the FUTURE 3 extension study. Of the 58 participants in the FUTURE 3 extension study, a total of 10 participants entered the exceptional use treatment period (EUTP). Data for 3 participants in China after 19 Nov 2019 was not included in the report to meet the Human Genetic Resources Administration Office (HGRAO) requirements.

Core + Extension

Reasons for not completing this period:

Exceptional Use Treatment Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the Safety population analysis set, including all patients who received at least one dose of study treatment and evaluated according to the study treatment that they received.

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 Treatment Emergent Adverse Events (AEs) up to 7 Days After Permanent Study Drug Discontinuation, measured over Up to 62 weeks in average.

The posted primary outcome is the number of participants with at least one treatment-emergent adverse event, serious or not serious, whether or not the event was judged causally related to study drug. The stated observation window extends through seven days after permanent study-drug discontinuation. The timeframe is described as up to 62 weeks in average, and the outcome description says events are presented cumulatively across FUTURE 3 and its extension.

This is a participant count: a person with one or more qualifying events contributes to the count of participants with an event. It does not describe the total number of event episodes, the duration of events, or their severity distribution. The description includes events regardless of causal attribution, so the count is a broad safety summary rather than a count of events established to have been caused by bosentan.

The endpoint has a special registry context. The record states that the extension was exploratory and that no primary efficacy and safety endpoints were defined in the protocol. This measure was therefore selected and reported as the primary endpoint in the registry. Its use gives readers a stated way to summarize observed safety events, but the label “primary” should not be taken to mean that it was prospectively designated in the protocol as the principal confirmatory outcome. A primary efficacy outcome is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical distinctions help interpret the posted results. The record presents a participant-count outcome: whether a participant had at least one qualifying event. This is a binary outcome because each participant is classified according to event status for the measure. Such a count does not preserve the number of recurrent episodes. A participant with multiple events may still contribute only once to a count of participants with at least one event.

What does a participant count show?

A participant count is a direct description of how many people met the endpoint definition in the analyzed group. The associated “at risk” count provides the group size used for that outcome display. These figures do not, by themselves, describe when events occurred, how long they lasted, whether the same person experienced several kinds of events, or how event burden varied between participants. The primary endpoint description also includes events whether or not they were considered causally related to study drug, so it should not be interpreted as a count of drug-attributed events only.

For time-to-event data, an analysis would usually use information about event timing and follow-up, rather than only a yes-or-no participant status. The primary outcome description in this record gives a cumulative participant count over its stated observation window; no time-to-event analysis for this endpoint is reported in the registry record. The average timeframe is stated as up to 62 weeks, but the record does not provide individual follow-up durations or explain how incomplete observation was handled.

Why does non-randomized allocation matter?

Random assignment is a design method intended to balance, across groups on average, both measured and unmeasured factors that may affect outcomes. That balance cannot be presumed for groups created without randomization. Here, the arm descriptions say participants continued the regimen received during the core study, and allocation is recorded as non-randomized. Factors related to prior treatment, clinical status, or the decision to continue a regimen could therefore differ across groups. The record does not report an adjustment strategy that would address such differences.

In an open-label study, treatment assignment is not masked. This may matter for event reporting, clinical assessment, and decisions during follow-up, depending on the outcome and study procedures. That is a general methodological consideration, not evidence that reporting was biased in this study. The registry does not report whether adverse events were adjudicated by an independent committee or whether particular safeguards were used to limit assessment differences.

What can uncertainty estimates tell readers?

A confidence interval is a statistical range used to express uncertainty around an estimate under a specified analysis. It can show which effect sizes are reasonably compatible with the observed data and the model assumptions. A narrow interval generally indicates more precision than a wide interval, while an interval spanning both meaningful benefit and harm may leave the direction uncertain. These are general explanations of confidence intervals; the registry record does not report a confidence interval for the primary outcome or a between-regimen effect estimate.

A p-value, when used, describes how compatible data are with a specified null model under the analysis assumptions. It is not the probability that a treatment works, nor does it measure the size or clinical importance of an effect. No p-value for a comparison of these groups is reported in the registry record. Without a prespecified inferential framework, a numerical difference in observed counts should not be treated as a definitive treatment contrast.

What do planning illustrations mean?

Sample-size planning uses assumptions about the effect a future study aims to detect, the allocation between groups, the significance level, and the statistical model. The record describes planning illustrations based on the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. Those assumptions describe a planning exercise, not the design justification for this extension. The record does not report that these assumptions were used to plan the trial, and it does not report a sample-size justification. Planning illustrations are not observed power and cannot establish whether the study had adequate power for a particular clinical question.

The record also describes a distinction for time-to-event planning: such calculations use a total number of events, whereas other planning displays use participants per arm. These are general planning conventions stated in the registry information; they do not change the interpretation of the posted participant counts. Any recalculated, unadjusted comparison based on summary data would also differ from a sponsor analysis if the two disagree. In that circumstance, the sponsor’s own analysis takes precedence. No recalculated comparison is described in the registry record used for this interpretation.

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("Bosentan 2mg/kg b.i.d.", "Bosentan 2mg/kg t.i.d.")
n      <- c(33, 31)
events <- c(29, 26)
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  Bosentan 2mg/kg b.i.d.  33  29  87.9  71.8  96.6  72.7  95.2  72.5  95.0
ARM  Bosentan 2mg/kg t.i.d.  31  26  83.9  66.3  94.5  67.4  92.9  67.2  92.8

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes, treatment contrasts, subgroups, or time points. If many statistical tests are conducted, the chance of at least one apparently notable result can increase unless the analysis plan accounts for the number and structure of tests. The registry lists 17 outcome measures and 8 analyses, but the statistical plan for prioritizing or adjusting among them is not reported in the registry record. The extension is described as exploratory, and the record says that no primary efficacy and safety endpoints were defined in the protocol. The safety outcome was selected and reported as primary in the registry.

The record does not report an approach to missing outcome data, including how participants without complete follow-up were handled, whether any values were imputed, or how censoring or discontinuation affected analyses. The endpoint window includes events through seven days after permanent study-drug discontinuation, but that definition alone does not explain the handling of missing observations. The average timeframe is reported as up to 62 weeks; individual observation times and the completeness of follow-up are not given.

The safety population is described as including all patients who received at least one dose of study treatment, evaluated according to the treatment they received. This is a stated analysis population definition for the safety measure. The registry does not report enough detail to establish how every analysis population was defined for all other outcomes, or whether efficacy analyses used the same population.

These omissions limit assessment of how outcomes and analyses were selected, how incomplete data may have influenced the counts, and how many statistical comparisons were considered. They do not establish that any particular method was or was not used; those details are simply not reported in the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pulmonary hypertensive crisis (20.0%), pulmonary arterial hypertension (12.1%), migraine with aura (10.0%), pneumonia (10.0%), respiratory tract infection viral (10.0%).

The serious adverse event figures are participant counts paired with the number listed as at risk in each group. The twice-daily group has 15 participants with serious adverse events among 33 at risk; the three-times-daily group has 13 among 31; and the group titled “Bosentan 2mg/kg b.i.d or t.i.d. During EUTP” has 4 among 10. These are registry counts, not estimates of comparative risk adjusted for differences between groups.

The registry lists deaths of 8, 4, and 1 for those groups, respectively. It does not state in this outcome entry that these deaths were caused by study treatment or that they were all classified as serious adverse events. Deaths should therefore be read as separately listed counts, not as treatment-attributed events.

The serious-event terms and percentages listed include pulmonary hypertensive crisis (20.0%), pulmonary arterial hypertension (12.1%), migraine with aura (10.0%), pneumonia (10.0%), respiratory tract infection viral (10.0%), and haemoptysis (10.0%). The registry does not explain the denominators underlying these percentages or whether terms refer to participants or event reports. The percentages should not be used to infer counts or compare groups.

Because allocation was non-randomized, and the record identifies the extension as exploratory, these figures describe reported experience rather than establish a causal difference between dosing regimens.

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

The results describe a safety outcome selected and reported as primary in the registry for an exploratory extension. They show the posted counts of participants with serious and other adverse events in the listed treatment groups, along with separately listed death counts. The primary endpoint’s definition is broad: it includes at least one event, whether serious or not, and does not require that the event be judged causally related to study drug.

These data do not establish that bosentan caused an event, or that a particular regimen caused more or fewer events than the other. The groups were not randomized, and the registry explicitly warns that they are not a like-for-like control comparison. The counts also do not reveal how many events each participant had, the timing or duration of events, or the uncertainty around a between-group contrast. Comparative effect estimates, confidence intervals, and p-values are not reported in the registry record.

The endpoint cannot be treated as a primary efficacy result. Although the study objectives included efficacy, the registry states that the extension was exploratory and that no primary efficacy and safety endpoints were defined in the protocol. Efficacy results are not reported in the registry record. The endpoint’s registry label therefore describes how it was selected for reporting, not a protocol-defined confirmatory claim.

The record is also limited in its explanation of the additional group titled “Bosentan 2mg/kg b.i.d or t.i.d. During EUTP,” the denominators for the serious-event term percentages, missing-data handling, and analysis choices across outcomes. Those details matter for understanding precisely which participants and observations underlie a result. The posted information can support a careful description of reported counts, but not a definitive causal comparison or a broad conclusion about treatment efficacy.

14. Why This Trial Matters Statistically

This extension illustrates why statistical interpretation depends on design as well as on the observed counts. A comparison of two dosing regimens can appear straightforward, but continued regimens in a non-randomized, open-label extension do not create a randomized contrast. The registry’s warning that the arms are not a like-for-like control comparison is central: group differences may reflect factors other than regimen, and the posted counts alone cannot separate those possibilities.

The record also makes a useful distinction between an outcome called “primary” in a registry entry and an endpoint defined as primary in a protocol. The extension is described as exploratory, with no protocol-defined primary efficacy and safety endpoints; the safety measure was selected and reported as primary. That distinction matters when readers assess whether the analysis was confirmatory or descriptive.

For biostatisticians and clinical researchers, the endpoint’s construction also deserves attention. It counts participants with at least one event, combines serious and non-serious events for the primary definition, includes events regardless of causal attribution, and covers the core study and extension cumulatively. Those design choices determine what the outcome can answer and what information it leaves out, such as event frequency per participant or timing.

Finally, the record demonstrates the importance of transparent reporting about analysis populations, missing observations, outcome selection, and denominators. Where those details are not reported, readers should avoid filling gaps with assumptions. The available information supports a bounded interpretation of safety counts, not a causal efficacy conclusion.

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 main limitation for interpretation is the non-randomized comparison. Participants continued the regimen received in the core study, so the groups may differ for reasons that are not described in the registry. The study is also open-label, and the record does not describe masking or independent event adjudication beyond listing no masking. These design features limit causal interpretation of any differences in reported outcomes.

The endpoint description combines observations from FUTURE 3 and its extension and includes events through seven days after permanent study-drug discontinuation. The registry does not provide enough detail to separate core-study events from extension events, describe individual follow-up, or explain handling of incomplete observation. Although the average timeframe is stated as up to 62 weeks, the record does not give further detail on follow-up distribution.

The registry includes an additional group titled “Bosentan 2mg/kg b.i.d or t.i.d. During EUTP,” but its relationship to the continued twice-daily and three-times-daily groups is not reported. The record also does not explain the denominator basis for the serious adverse event term percentages. The listed group counts should not be combined to create an overall total or treated as mutually exclusive without that clarification.

Other important statistical details are not reported in the registry record, including a protocol-defined primary endpoint, the sample-size justification, the handling of missing data, and an inferential comparison of the regimens. The extension is explicitly described as exploratory. These limitations mean that the posted results are best read as descriptive safety information, with no reported efficacy comparison or basis for a definitive causal claim.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: FUTURE 3 Study Extension — NCT01338415.
• Registry record last updated 2025-03-30; status last verified 2025-03.
• Results first posted 2017-12-11.
• 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

FUTURE 3 Study Extension (NCT01338415) is listed as a completed Phase 3, prospective, multicenter, open-label, non-randomized extension study in children with pulmonary arterial hypertension. The registry describes continued bosentan dosing at 2 mg/kg twice daily or three times daily, with participants remaining on the regimen received during the FUTURE 3 core study. Enrollment is listed as 58.

The posted primary safety outcome counts participants with at least one treatment-emergent adverse event, serious or not serious, regardless of causal relation to study drug. Events are presented cumulatively across the core study and extension and include the period through seven days after permanent study-drug discontinuation. The registry states that the extension was exploratory, with no primary efficacy and safety endpoints defined in the protocol; this safety measure was selected and reported as primary.

Serious and other adverse-event counts, death counts, and selected serious-event terms are listed by group. Because allocation was non-randomized and the registry cautions that the arms are not like-for-like controls, the counts are descriptive rather than a causal treatment comparison. Efficacy findings and further statistical analysis details are not reported in the registry record.