Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH (NCT00439946), a na phase 4 study. The primary outcome is Change From Baseline at Week 8 in 6-Minute Walk Distance (6MWD).

2. Clinical Question

The study title and summary describe a rapid switch from intravenous epoprostenol, or Flolan, to intravenous treprostinil, or Remodulin, using the Crono Five pump. The stated focus includes safety, efficacy and treatment satisfaction. The registry also lists secondary outcomes concerning dyspnea after the walk test, World Health Organization functional classification, and symptoms including fatigue, dyspnea, edema, orthopnea, dizziness and syncope.

Because there is no control group, the primary question is descriptive: what change was observed among participants with the relevant measurements? A within-group change cannot, by itself, separate changes associated with the switch from other influences over time. The registry record does not report a numerical primary estimate, so the direction and size of the recorded change cannot be described.

3. Trial Design

The registry describes a Phase 4, single-group study of switching from intravenous Flolan to intravenous Remodulin in people with stable PAH. The planned study period in the brief summary is 8 weeks. The listed intervention is continuous intravenous treprostinil through the Crono Five ambulatory infusion pump. The summary contrasts this pump and treatment arrangement with the Flolan regimen participants were switching from; it describes the study’s interest in safety, exercise performance, treatment satisfaction and quality of life.

The allocation is recorded as not applicable, masking as none, and the model as single group. These features mean the study is not a randomized comparison and has no like-for-like control arm. Any changes measured between baseline and Week 8 describe the group’s course during the study; they do not provide a randomized estimate of what would have happened without the switch.

Enrollment is listed as 8. The record gives a start of 2007-02, primary completion of 2009-09 and status of terminated. The reason for termination is not reported in the registry record. The record does not establish from these registry entries whether all enrolled participants completed follow-up or received every planned assessment.

The primary outcome is change from baseline at Week 8 in 6-minute walk distance (6MWD), measured in meters and specified as a mean with standard deviation. The record says two subjects lacked baseline 6MWTs and were excluded from this analysis. It does not report the number contributing Week 8 data or further details of the primary analysis. The record lists 14 outcome measures and 23 analyses, but does not describe the statistical plan used to select or interpret those analyses.

With no allocation to different treatment groups, comparisons between arms and masking-related protections against knowledge of assigned treatment do not apply. The registry does not report a protocol-level sample-size justification, interim analysis plan, or detailed analysis populations. These absences limit what can be inferred about the study’s design decisions beyond the single-group structure and listed outcome definitions.

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: A total of ten subjects were screened. Eight were enrolled and completed the study. One subject withdrew their consent prior to enrolling. The second subject failed screening due to low hemoglobin levels. Once enrolled, baseline assessments were completed, and patients underwent rapid switch from epoprostenol to treprostinil infusion.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Two subjects did not have Baseline 6MWTs and were excluded from this analysis.

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 Change From Baseline at Week 8 in 6-Minute Walk Distance (6MWD), measured over Week 8.

The primary endpoint is change from baseline at Week 8 in 6-minute walk distance, reported in meters. The 6-minute walk test measures the distance a participant can walk during a specified six-minute period. In general, it is used as a standardized measure of functional exercise capacity; it is not a direct measure of every aspect of PAH symptoms, daily functioning or quality of life.

The registry says that administration of the test and specifications of the testing area followed American Thoracic Society guidelines and the investigative site’s usual practice, citing ATS guidelines from 2002. Standardized testing procedures can help make repeated measurements more comparable, though results may still be influenced by participant condition, test execution and other factors.

A change score compares a participant’s Week 8 measurement with their baseline measurement. The registry specifies a mean and standard deviation as the summary statistics, but does not report the mean change or its variability. The numerical result, any confidence interval, and any test of statistical significance are not reported in the registry record. Two subjects without baseline 6MWTs were excluded from the primary analysis; the record does not say how missing Week 8 measurements were handled.

As a single-group endpoint, the change can describe what happened between assessments among participants included in the analysis. It cannot, on its own, establish that the switch caused the change. The absence of a concurrent comparator also means that the endpoint does not quantify a difference between switching and continuing the previous treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measurement: change in walking distance, in meters. The registry specifies that it is summarized by a mean and standard deviation. In general, a mean gives the arithmetic average of a set of measurements, while a standard deviation describes how spread out individual measurements are around that average. These summaries answer different questions: the mean describes the group’s average change, and the standard deviation describes variability among individual changes. Neither statistic is reported numerically for the primary outcome in the registry record.

A change-from-baseline analysis uses each participant’s baseline and follow-up measurement to describe movement over time. In general, analyzing paired measurements can account for the fact that two measurements from the same participant are related. The registry names the change endpoint but does not report the detailed calculation, any model used, or how the analysis accounted for incomplete measurements. The record says that two participants without baseline 6MWTs were excluded from this analysis.

A confidence interval, in general, expresses the uncertainty around an estimate under a specified statistical method. A narrower interval indicates greater precision under that method, while a wider interval indicates less precision. A confidence interval is not reported for the primary outcome in the registry record. Without an estimate and its uncertainty, the magnitude and precision of the primary result cannot be assessed. A p-value, also not reported for that outcome, would address compatibility with a specified null hypothesis under model assumptions; it would not measure the size or clinical importance of a change.

The single-group design is central to interpreting the analysis. In general, a before-and-after comparison can describe temporal change, but it does not provide the same causal protection as a randomized comparison. Factors that change over time, test familiarity, or regression to the mean may contribute to a measured difference. These are general considerations, not findings reported for this study. The registry does not report an analysis designed to distinguish such influences from an effect of switching treatment.

The study lists multiple outcomes and analyses. In general, when many hypotheses are tested, the chance of obtaining at least one apparently unusual result by chance can increase if each test is interpreted without regard to multiplicity. Adjustment procedures or a prespecified hierarchy can address some multiplicity concerns. The registry record does not report whether any adjustment, hierarchy or other multiplicity strategy was used. The list of outcomes and analyses alone does not reveal which analyses were prespecified or how results were interpreted.

Dispersion matters because a group mean can conceal substantial differences among participants. In general, continuous outcomes may have more variability than a simple normal model assumes; over-dispersion means greater variability than the model allows and can make model-based uncertainty estimates too small if ignored. That is a general statistical issue, not a documented feature of this outcome. The registry specifies standard deviation for the primary measure but does not report a distributional assessment or the method used to estimate uncertainty.

The study record includes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustration considers detecting stated fractions of the observed effect. For time-to-event outcomes, the planning convention is total events; for other outcomes, it is participants per arm. These are planning illustrations, not observed power and not the study’s own design justification. The registry does not report that the trial was designed as a two-arm study, and its actual model is single group. The record does not report a protocol-based sample-size calculation or the assumptions used to plan the original study.

Planning calculations describe how much information a hypothetical future design might require under stated assumptions. In general, such calculations depend on the target effect, variability, significance level, power, allocation and analysis method. A planning illustration derived from an observed effect is especially dependent on the estimated effect, which can be unstable in a small study. It should not be read as proof that the original study had adequate power, nor as evidence that a future study will produce the same effect.

The registry provides no detailed description of the primary statistical test, covariate adjustment, missing-data method, confidence-interval method, or analysis population beyond the stated exclusion for missing baseline tests. Each of those choices can affect estimates or their uncertainty. In the absence of those details and the numerical outcome, methodological interpretation must remain limited to the endpoint definition, summary measure and exclusions explicitly recorded.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Treprostinil")
n   <- c(6)
m   <- c(-1.2)
sp  <- c(37)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Treprostinil  6  -1.200  37.000  -40.029  37.629

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures and 23 analyses, including the primary 6MWD outcome and multiple symptom and functional measures. When many outcomes or analyses are examined, general statistical practice recognizes a multiplicity concern: interpreting each result as if it were the only test can increase the chance of false-positive findings across the full set. The registry record does not report whether analyses were prespecified in a hierarchy, whether significance levels were adjusted, or whether any other multiplicity strategy was used. Numerical results for the listed secondary outcomes are not reported in the registry record.

For the primary analysis, two subjects did not have baseline 6MWTs and were excluded. The record does not report why their baseline tests were absent, how many participants had missing Week 8 measurements, or how any additional missing values were handled. It also does not report imputation, sensitivity analyses, or an intention-to-treat definition. These details matter because an analysis based only on observed measurements can represent a selected subset if missingness is related to participants’ health or outcomes. Whether that concern applies cannot be determined from the record.

The primary analysis population is therefore only partly described: the stated baseline-test exclusion is known, but other inclusion rules and the number contributing follow-up data are not reported in the registry record. The record also does not describe analysis populations for safety or secondary outcomes. These gaps limit assessment of how complete the analyses were and how robust findings might be to alternative missing-data assumptions.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: central line infection (12.5%), fluid overload (12.5%), hyperkalaemia (12.5%), right ventricular failure (12.5%).

For the treprostinil group, the registry reports serious adverse events among 3 participants at risk of 8, and other adverse events among 8 participants at risk of 8. The record lists central line infection, fluid overload, hyperkalaemia and right ventricular failure among the serious adverse event terms, each reported as 12.5%. These are descriptive safety figures from this study; they are not a comparison with an untreated or alternative-treatment group.

The percentages attached to serious event terms should be read as reported, not as evidence about whether terms occurred in the same or different participants. The registry record does not specify that overlap, nor does it provide detailed event timing, severity grading or causal attribution. A report of an event during the study does not by itself establish that the treatment or pump caused it.

Deaths are not reported in the registry record. Because the study has no control group and the enrollment is listed as 8, these counts cannot determine how the event frequency compares with another treatment or with the underlying risk in a broader PAH population. They describe what the registry reports for this study, not a general estimate of safety.

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

The registry record establishes that a small, single-group study was conducted to examine a switch from intravenous Flolan to intravenous Remodulin delivered using the Crono Five ambulatory pump. Its primary outcome was change from baseline in 6-minute walk distance at Week 8. The record also identifies safety, symptoms, functional classification, treatment satisfaction and quality of life as areas of interest.

The numerical primary result is not reported in the registry record. As a result, the direction and size of change in 6MWD cannot be stated, and its statistical precision cannot be assessed. The absence of a reported result is not evidence that there was no change. Nor can the record support a claim that the switch improved or worsened the endpoint.

The design does not include randomization or a control group. Even with a reported baseline-to-follow-up difference, the study could describe change over time but would not by itself establish that the switch caused it. A comparison with continued Flolan or another treatment would require an appropriate comparator and analysis; neither is part of the registered design.

The safety counts describe events recorded in the treprostinil group, without a comparison arm. They do not establish causation or quantify how risk differs from another treatment. The missing baseline tests, unreported follow-up completeness, and absent details about missing-data handling also restrict assessment of the outcome analysis.

Overall, the record is informative about the study question, intervention, endpoint and several design features. It is insufficient for a numerical efficacy conclusion or a comparative safety conclusion. The record does not report the reason for termination, a detailed statistical plan, or numerical results for the primary and secondary outcomes.

14. Why This Trial Matters Statistically

This study raises a statistical question common in treatment-switch research: how should change be described when participants move from one treatment to another but there is no concurrent control group? A before-and-after endpoint can be useful for documenting what happened during the transition. Its interpretation remains different from a randomized comparison because time-related changes and other influences cannot be separated from the switch by the design alone.

The endpoint also illustrates the distinction between an outcome’s definition and its result. The registry specifies a Week 8 change in 6-minute walk distance, with the mean and standard deviation as summaries. Yet without the numerical estimate and its uncertainty, readers cannot judge the size, direction or precision of the result. A clearly defined measure does not substitute for a posted estimate.

The record’s exclusion of two participants without baseline 6MWTs highlights another practical issue: analysis populations depend on measurement availability. Missing measurements may reduce information and can affect interpretation, depending on why they are absent. The registry does not report enough detail to determine the impact of missingness.

Finally, the listed 14 outcome measures and 23 analyses make transparent reporting of analysis choices important. Prespecification and multiplicity handling help readers understand how a collection of results should be interpreted, but those methods are not reported in this record. The study therefore illustrates why design, missing-data details, outcome estimates and analysis plans all matter alongside the clinical question.

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 interpreting the endpoint is that its numerical result is not reported in the registry record. There is no reported estimate of mean change, standard deviation, confidence interval or p-value. The study’s direction and magnitude of change, and the precision of any estimate, therefore cannot be assessed from the record.

The single-group design has no randomized control group. It can describe change over time among those measured but cannot isolate the effect of switching from other influences. Masking is recorded as none, and the registry does not report further protections against measurement or reporting bias.

The enrollment is listed as 8, and two participants without baseline 6MWTs were excluded from the primary analysis. The record does not report the number with Week 8 measurements, reasons for missing tests, or how any other missing data were handled. The primary analysis population is consequently not fully characterized.

Although the registry lists multiple secondary outcomes and analyses, it does not report their numerical results, a multiplicity plan, or which analyses were prespecified. The reason for the terminated status is not reported in the registry record. The detailed statistical plan, original sample-size justification, interim analyses and analysis-population definitions are also not reported. These limitations are specific to what is documented and do not establish that any unreported procedure was or was not performed.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH — NCT00439946.
• Registry record last updated 2024-01-03; status last verified 2013-06.
• Results first posted 2013-07-17.
• 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

This Phase 4 study examined switching from intravenous Flolan to intravenous Remodulin in people with stable PAH, using the Crono Five ambulatory infusion pump. It is listed as single group, with allocation not applicable and masking none. Enrollment is listed as 8; study status is terminated.

The primary outcome was change from baseline at Week 8 in 6-minute walk distance, measured in meters and summarized as a mean with standard deviation. Two subjects without baseline 6MWTs were excluded from that analysis. Its numerical result is not reported in the registry record. The record also lists symptom and functional outcomes, as well as serious and other adverse event counts, but does not provide numerical results for the primary endpoint or detailed analysis methods.