Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID) (NCT02847260), a na phase 4 study. The primary outcome is Number of Participants With Successful Completion of the 16 Week Treatment Period..

2. Clinical Question

RAPID was a Phase 4 study described as open label and multi-centre. Its stated purpose was to evaluate the safety and tolerability of rapid dose titration of subcutaneous Remodulin in people with PAH. The registry record also lists pharmacodynamic effects as part of the study's broader evaluation. Because there was no control group, the study's design can describe outcomes observed during the regimen but cannot isolate the regimen's effects from other influences through a randomized between-group comparison.

3. Trial Design

RAPID (NCT02847260) was a completed Phase 4, open-label, multi-centre, single-group study. Its official title describes a 16 Week study of the safety, tolerability and pharmacodynamic effects of a rapid dose titration regimen of subcutaneous Remodulin in people with PAH. The registry lists enrollment of 39. The study start is recorded as 2012-04 and primary completion as 2014-03.

All participants were assigned to the Remodulin group; the record does not list a control arm. Allocation is recorded as NA, masking as none, and the study model as single group. In an open-label study, treatment is not masked from participants or investigators. The registry does not report whether outcome assessment used any additional blinding procedures.

The arm description says Remodulin was initiated while participants were hospitalized, with a minimum stay of 72 hours, and under medical supervision. The stated starting dose was approximately 2 ng/kg/min as a continuous subcutaneous infusion. Dose increments of 1-2 ng/kg/min were applied approximately every 12 hours according to clinical response and tolerability. The available arm description ends before its full account is complete, so later dosing or follow-up details are not reported in the registry record.

The primary endpoint was successful completion of the 16 week treatment period, defined using both completion and an investigator-attributed serious adverse event condition. Listed secondary outcomes include six minute walk distance, Borg Dyspnea Score after the walk test, NT-proBNP concentrations, WHO functional classification, CAMPHOR quality of life assessment, and hemodynamic measures. These include PAPm, RAPm, PCWPm, cardiac index and PVRI. Numerical results for these outcomes are not reported in the registry record. The record lists no analyses.

As a single-group study, RAPID can report experiences and measurements among participants treated under its regimen, but it does not offer a like-for-like randomized control comparison. Its design should be read as descriptive and exploratory with respect to outcomes, rather than as a comparative test of treatment strategies.

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

Reasons for not completing this period:

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 Participants With Successful Completion of the 16 Week Treatment Period., measured over Baseline to week 16.

The primary endpoint is the number of participants who successfully completed the 16 week treatment period. Success was defined as completing that period without experiencing a serious adverse event considered by the investigator to be possibly related to Remodulin. This combines a completion requirement with a safety-related attribution requirement; meeting only one part would not satisfy the stated definition.

An endpoint of this kind can provide a direct summary of whether participants remained in the study through its planned treatment period without the specified safety event. It is relevant to a study focused on safety and tolerability during rapid dose titration. It is narrower than a complete account of safety: it does not count every adverse event as a failure, and the definition depends on the investigator's assessment of whether a serious event was possibly related to the drug. The record separately lists serious and other adverse event figures.

The endpoint does not measure a randomized treatment effect, because the study had no concurrent control group. Nor does the success definition itself measure symptom change, exercise capacity, quality of life or hemodynamic response; those topics appear among the secondary outcomes. The registry record does not report the number of participants who met the primary definition, so the endpoint's observed result cannot be described from the registry information available.

For interpretation, it is important to distinguish the endpoint definition from its result. The definition is reported, but the result, any uncertainty interval, and details of the population included in the endpoint analysis are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

RAPID uses a single-group design. This means the listed study group received the intervention, rather than being allocated between intervention and control groups. The registry records allocation as NA and masking as none. In general, a randomized comparison helps distinguish differences associated with treatment assignment from differences that can arise through participant characteristics, time trends or other care. Without such a comparator, an outcome observed in the Remodulin group is descriptive of that group and does not estimate a randomized treatment contrast.

What does open label mean?

Open label means that treatment assignment is not concealed from participants and investigators in the way it would be in a masked study. Knowledge of treatment can affect reporting, decisions about care, follow-up and judgments about whether an event is related to treatment. This is particularly relevant to the primary endpoint, because the definition relies partly on an investigator's judgment that a serious adverse event was possibly related to Remodulin. The registry record does not report whether independent adjudication or other safeguards were used for this judgment.

What does the primary endpoint count?

The endpoint is a count of participants meeting a defined condition, not a continuous measurement such as walking distance or a biomarker concentration. Success requires both completion of the 16 week treatment period and absence of a serious adverse event considered possibly related to Remodulin. The record does not report the observed count, an estimate of its uncertainty, or the analysis population used. Without those details, the endpoint can be explained but not statistically evaluated from the registry record.

How should event counts and percentages be read?

Adverse event summaries describe reported safety experiences, but their interpretation depends on the precise unit and rules used to tabulate them. A participant may experience more than one event or more than one listed event term. Consequently, event categories may overlap, and percentages for individual terms should not be added to create an overall proportion. The registry lists serious and other adverse event figures and several serious-event terms, but does not report the detailed coding, attribution, recurrence or overlap information needed to reconstruct event-level analyses.

Why do uncertainty intervals matter?

General statistical explanation: an estimate summarizes observed data, while a confidence interval describes the range of values compatible with the data under a specified statistical model and procedure. It helps readers assess precision; a point estimate alone does not show how uncertain an estimate is. The registry record does not report a primary endpoint estimate or confidence interval, nor does it report intervals for the listed secondary outcomes. Precision therefore cannot be assessed from the information recorded.

What can the secondary outcomes contribute?

The secondary outcomes cover different domains: six minute walk distance, Borg Dyspnea Score after the walk test, NT-proBNP, WHO functional classification, CAMPHOR, and hemodynamic parameters. These measures are not interchangeable. Some are continuous measurements, while the functional classification outcome is described as a number of participants with a change. Each would require a clearly specified analysis and population to support interpretation. The record lists outcome definitions but does not report numerical results, analysis methods or estimates of uncertainty for them.

How does multiplicity affect interpretation?

General statistical explanation: when several outcomes or tests are examined, the chance of at least one apparently unusual result can increase if each is interpreted independently using the same threshold. A prespecified hierarchy or adjustment can address this issue, while descriptive reporting can present outcomes without treating each as a confirmatory test. The registry lists multiple secondary outcomes but does not report a multiplicity strategy, testing hierarchy or statistical analysis plan. It is therefore not possible to determine how multiple outcomes were handled.

What does over-dispersion mean for count outcomes?

General statistical explanation: over-dispersion occurs when observed variability in count data exceeds what a chosen statistical model expects. If a model does not account for that extra variation, standard errors and uncertainty assessments can be misleading. This concept may matter in studies analyzing repeated events or counts, but the registry does not report such a model for RAPID. No count-model specification or analysis result is available in the registry record, so no claim about over-dispersion or its handling can be made.

Are the planning assumptions the study's analysis?

The statistical planning description refers to an illustration using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with an effect defined as a stated fraction of an observed effect. Time-to-event illustrations are described in terms of total events, while other illustrations are described in participants per arm for 80% power. These are planning conventions, not reported results from RAPID. They do not change the actual single-group design, do not establish observed power, and do not supply an estimate of the study's outcome. The registry does not report numerical planning outputs or a trial-specific sample-size justification.

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("Remodulin")
n      <- c(39)
events <- c(32)
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  Remodulin  39  32  82.1  66.5  92.5  67.3  91.0  67.2  90.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and multiple secondary outcomes. The secondary outcomes cover exercise capacity, dyspnea, NT-proBNP, WHO functional classification, quality of life and hemodynamic measures. When several outcomes are assessed, general statistical practice distinguishes a prespecified primary question from additional outcomes and considers whether formal testing across outcomes requires a hierarchy or adjustment. The registry record does not report a multiplicity strategy, a testing hierarchy or a statistical analysis plan. It is not possible to determine whether secondary outcomes were treated as exploratory or inferential in the study's analyses.

Missing-data handling is also not reported in the registry record. The primary endpoint requires treatment-period completion, but the record does not specify how withdrawals, unavailable endpoint assessments or other incomplete observations were handled in analysis. It does not report whether analyses used all enrolled participants, only participants with observed outcomes, or another defined population. The analysis populations and denominators for the secondary outcomes are likewise not reported.

The registry lists no analyses and does not provide numerical primary or secondary outcome results. It therefore offers no basis to assess model assumptions, adjustment for baseline measurements, sensitivity analyses, imputation procedures or the handling of protocol deviations. These details should not be inferred from the fact that the study is marked completed or from the listed outcome definitions. Their absence limits assessment of both potential bias and the robustness of any result.

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: right ventricular failure (rvf) (7.7%), fluid overload (5.1%), diarrhoea, (5.1%), nausea (5.1%), infusion site pain (5.1%).

The registry reports 11 participants with serious adverse events among 39 at risk in the Remodulin group. It also reports 39 participants with other adverse events among 39 at risk, and 0 deaths. These are safety summaries, not estimates from a randomized comparison, because the study had a single group and no concurrent control.

The listed serious adverse event terms and percentages are Right Ventricular Failure (RVF), 7.7%; Fluid Overload, 5.1%; Diarrhoea,, 5.1%; Nausea, 5.1%; Infusion Site Pain, 5.1%; and Rib Fracture, 2.6%. The record does not specify whether these percentages refer to participants or event occurrences, nor whether individuals could contribute to multiple terms. The terms should therefore be read as registry-listed safety information, not as exclusive categories that can be combined.

The adverse event summary does not show which events investigators considered possibly related to Remodulin, how many participants completed the treatment period, or how many met the primary endpoint definition. Attribution, timing, severity details beyond the serious-event classification, and event-level follow-up are not reported in the registry record. These figures describe what the record reports; alone, they do not establish causation or provide a comparison with another regimen.

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

RAPID addresses a practical statistical question: what outcomes and safety events were recorded while people with PAH received subcutaneous Remodulin under a rapid dose titration regimen. The registry identifies a primary endpoint focused on completing the 16 week treatment period without a serious adverse event judged possibly related to Remodulin. It also records safety summaries and a set of secondary measures across functional, symptom, biomarker, quality-of-life and hemodynamic domains.

The record does not report the result for the primary endpoint. It therefore does not show how many participants met the success definition, and it gives no estimate or interval with which to judge the precision of that outcome. Numerical results for the listed secondary outcomes are also not reported. The safety summaries do report 11 participants with serious adverse events, 39 with other adverse events, and 0 deaths, but they do not supply all the attribution and endpoint details needed to interpret these figures as a treatment effect.

Because RAPID had a single group and no randomized comparator, it cannot establish from a between-group contrast whether rapid titration caused a particular outcome. Even if changes from baseline had been reported, changes over time in a treated group would not by themselves separate the treatment's contribution from other influences. The registry does not report the analyses needed to examine such changes in any case.

The findings that can be described are therefore limited to the study's design, endpoint definitions, outcome domains and posted safety summaries. The record does not establish comparative benefit, comparative risk, or the size and precision of change in secondary outcomes. It also does not provide enough detail to assess missing observations, analysis populations or how investigator attribution was applied. These limits are important when distinguishing the study's purpose from what its registry record actually documents.

14. Why This Trial Matters Statistically

RAPID is statistically notable because its central question concerns tolerability during a defined treatment period, while its primary endpoint combines study completion with an investigator's assessment of possible treatment relatedness for serious adverse events. That definition makes clear what the study intended to count, but interpretation depends on both observed completion and event attribution. The registry record does not report the primary endpoint count or the details of attribution, leaving the central statistical result unresolved.

The single-group design also illustrates the distinction between describing outcomes and estimating comparative effects. A treated group can provide information about reported experiences during treatment, but it does not supply a concurrent counterfactual comparison. This matters when readers encounter outcomes such as changes in walking distance, symptoms, biomarkers or hemodynamic measurements: without reported results, analysis details and a control group, neither the magnitude nor the cause of change can be assessed from the record.

The breadth of the secondary outcome list makes multiplicity and analysis transparency relevant. Several domains are identified, but the registry does not report how they were prioritized, tested or handled when data were missing. The absence of posted analysis results also prevents examination of precision and consistency across outcomes. These are not merely reporting details; they determine what conclusions can be supported and how confidently.

Finally, the safety summaries show why event definitions and denominators matter. Serious events, other events, deaths and the primary endpoint are related but distinct summaries. The registry's figures cannot be combined into a complete account of treatment completion or attribution. The trial is useful for understanding a specific study design and its reported safety data, while the missing endpoint and analysis results sharply limit statistical conclusions.

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 most immediate limitation is that the registry record does not report the observed primary endpoint result. Although successful completion is defined, there is no count of participants meeting that definition or estimate of its precision. Numerical results for the secondary outcomes are also not reported, so the planned assessments cannot be evaluated as observed changes.

The single-group design provides no concurrent randomized control. This limits causal interpretation and prevents a like-for-like comparison with another dose titration strategy. The study is open label, and the primary endpoint includes investigator judgment about whether a serious adverse event was possibly related to Remodulin. The record does not report whether this judgment was independently reviewed or how attribution decisions were standardized.

Safety details are incomplete for interpretation. The record reports serious and other adverse event counts and selected serious-event terms, but does not explain whether term percentages are based on participants or event occurrences, whether terms overlap, or which events were judged related to treatment. It also does not report the number completing the treatment period, withdrawals, or reasons for discontinuation.

The registry record does not report analysis populations, missing-data methods, statistical models, confidence intervals, a multiplicity approach or a statistical analysis plan. The arm description is incomplete, so the full treatment and follow-up procedures are not available in the record. These reporting gaps limit assessment of the endpoint, the robustness of analyses and the completeness of safety interpretation. They should not be filled by assumptions about the protocol or by treating the planned outcome list as results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID) — NCT02847260.
• Registry record last updated 2017-10-17; status last verified 2017-09.
• Results first posted 2017-09-08.
• 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

RAPID (NCT02847260) is a completed Phase 4, open-label, multi-centre, single-group study of rapid dose titration of subcutaneous Remodulin in people with PAH. The registry lists enrollment of 39, a study start of 2012-04 and primary completion in 2014-03. The primary endpoint is successful completion of the 16 week treatment period without a serious adverse event considered possibly related to Remodulin.

The registry reports 11 participants with serious adverse events among 39 at risk, 39 with other adverse events among 39 at risk, and 0 deaths. It lists several serious adverse event terms with percentages. The primary endpoint result, numerical secondary outcome results, analysis populations, missing-data methods and statistical analysis plan are not reported in the registry record. With no concurrent comparator, the design supports description of the treated group, not a randomized estimate of comparative effects.