Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil (NCT03399604), a na phase 3 study. The primary outcome is Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events.

2. Clinical Question

The central statistical question is descriptive: how many participants in the registry’s reported groups were recorded as having serious or other adverse events? The primary outcome is an incidence measure expressed as participant counts. The record also says events were to be grouped by MedDRA System Organ Class, dose level, time on drug, and relationship to dose titration. It does not report a comparative hypothesis or an inferential analysis for those group differences.

The study’s stated follow-up began with baseline and included visits at Week 2, Month 1, and Month 2, followed by bimonthly follow-up for up to 16 months. That framework concerns event observation over time; it does not mean that every participant had the same observed duration. Individual follow-up duration and the timing of specific events are not reported in the registry record. The posted counts therefore address what was recorded in the described groups, rather than a controlled estimate of the effect of LIQ861 relative to another treatment.

3. Trial Design

This completed Phase 3 study is titled as an open-label, multicenter evaluation of the long-term safety and tolerability of inhaled LIQ861 treprostinil in patients with PAH. The registry classifies its model as single-group, masking as none, and allocation as NA. Enrollment is listed as 121. The record gives a study start date of 2018-01-02 and a primary completion date of 2019-05-06.

LIQ861 is described as a dry powder formulation delivered using the RS00 Model 8 dry powder inhalation device. Capsule strengths were 25 μg, 50 μg, 75 μg and 100 μg; the stated individual dose range was 25 μg to 150 μg treprostinil QID. The record identifies two groups in the adverse-event results: LIQ861 Add-On and Tyvaso Transition. It also says participants in the PK study were part of the transition group and were not analyzed separately for adverse events.

The two named groups do not make this a randomized comparison. Allocation is NA, and the design is open-label, so the registry does not establish that group membership was assigned randomly or that the groups were intended as exchangeable controls. The record does not report how participants entered either group, whether baseline characteristics differed, or how the groups’ treatment histories compared. It is therefore appropriate to describe the group-specific event counts, but not to interpret a difference between them as a causal treatment contrast.

The primary objective was long-term safety and tolerability. The registry lists one primary outcome measure, concerning treatment-emergent adverse events and serious adverse events. Its stated timeframe includes early visits and bimonthly follow-up for up to 16 months. Detailed operational rules for event onset, follow-up completion, or handling of treatment discontinuation 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: Of the 146 subjects screened for the study, 121 (55 Transition Group, 66 Add On Group) were enrolled.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The Safety Population included all subjects who received at least 1 inhalation of LIQ861.

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: All enrolled subjects were included in the Safety Population. The Efficacy Population included all but 1 subject (who had no post-Baseline efficacy assessments performed and was lost to follow-up. The mITT Population, which included all subjects identified as WHO Group 1 based upon adjudication by a panel of PAH experts, comprised 106 subjects. The PK Population included 18 subjects in the Transition Group.

6. Primary Endpoint

The registry lists the primary outcome as Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events, measured over Baseline, Week 2, Month 1, Month 2 Visits, with bimonthly follow up for up to 16 months..

The primary endpoint is the incidence of treatment-emergent adverse events and serious adverse events, measured in participants. In this registry record, the outcome type is a count of participants with an event. A participant count answers how many people in a stated group were recorded with the event category; it is not a count of all event episodes. One person may experience more than one event, and participant counts alone do not convey the total number of episodes, their duration, or their severity beyond the serious-event classification.

Safety endpoints of this kind are used to describe unwanted events observed during exposure and follow-up. Serious adverse events are an important safety category, while other treatment-emergent adverse events provide a broader account of events recorded after treatment began. The registry says events were to be organized by MedDRA System Organ Class, dose level, time on drug, and relationship to dose titration. The posted outcome information does not provide a complete breakdown across all of those dimensions.

The specified observation period runs from baseline through Week 2, Month 1, and Month 2 visits, with bimonthly follow-up for up to 16 months. This is a stated follow-up schedule, not a guarantee that each participant contributed the same observation time. A participant count is not a rate adjusted for time at risk. Individual event dates, person-time, and detailed rules for defining treatment emergence are not reported in the registry record, so the endpoint is best read as a descriptive safety count rather than a time-standardized comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry presents a safety endpoint in participant counts. The statistical reading therefore begins with the distinction between a participant who had an event and the total number of event episodes. A person-level count records whether participants were represented in an event category; it does not show how many episodes each person had. It also does not describe event duration, recurrence, or a rate over time. The registry’s outcome description identifies the unit as participants and the parameter as a count of participants.

What does a participant count tell us?

In general, a count is a direct descriptive summary of how many people meet an outcome definition in a group. A denominator gives context for that count, but a count alone does not establish a probability of causation. Here, the posted at-risk count is 121 for each adverse-event category in each named group. The registry does not supply an inferential estimate comparing the groups. No confidence interval or p-value for the adverse-event counts is reported in the registry record.

Counts also depend on how outcomes are defined and collected. The primary outcome concerns treatment-emergent adverse events and serious adverse events, but the detailed criteria used to decide whether an event was treatment-emergent are not reported in the registry record. The record states that events were to be grouped by MedDRA System Organ Class, dose level, time on drug, and relationship to dose titration. Those dimensions can help describe patterns, but a grouping plan is not the same as a complete posted set of results for every category.

Why does follow-up matter?

In general, people observed for longer have more opportunity for an event to be detected. Participant counts do not account for different lengths of observation. A rate-based analysis can incorporate time at risk, but the registry does not report an event rate, person-time, or a time-to-event estimate for this outcome. It gives a follow-up schedule of baseline, Week 2, Month 1, and Month 2 visits, followed by bimonthly follow-up for up to 16 months. The schedule does not establish the observed follow-up duration for each participant.

For time-to-event methods, the timing of events and the timing of the end of observation are essential. A participant without a recorded event may have completed observation without an event, may have stopped contributing data earlier, or may have had incomplete follow-up. The registry does not report enough detail to distinguish those possibilities or to reconstruct an exposure-adjusted analysis. No assumptions about censoring or event timing should be attributed to the study.

Can the group counts be compared as treatment effects?

In general, a causal comparison requires a design and analysis that address how participants came to receive each treatment or enter each group. Random assignment can support comparability, but this record lists allocation as NA and explicitly says the arms are not a like-for-like control comparison. It also identifies the study as open-label and single-group. Consequently, the group counts are descriptive, not an estimate of what would have happened to the same population under a different treatment.

Even when counts are presented side by side, their difference should not be given a causal interpretation without supporting design and analysis. The record does not report adjustment for baseline differences, a prespecified contrast, or an inferential model. No statistical analysis entries are listed. It is not possible to infer a statistical plan from the study’s Phase 3 label or from the presence of two group names.

What role do serious-event categories play?

In general, serious adverse events are a subset of safety information classified using seriousness criteria, whereas other adverse events provide a broader category. The posted results give group-level counts for serious and other adverse events and list selected serious-event terms with percentages. These summaries answer different descriptive questions: group counts describe participants in broad categories, while term-level percentages indicate the reported frequency attached to particular event terms. The registry does not provide the full participant-level data needed to determine overlap among terms or recreate the summaries.

The record does not report confidence intervals, hypothesis tests, adjustment methods, or a statistical model for the primary safety outcome. It also does not describe missing-data methods, multiplicity procedures, or a planned interim-analysis approach. Those methods should not be inferred from general practice. The statistical interpretation is therefore limited to the descriptive information entered in the registry and general principles for reading counts, follow-up, and nonrandomized groups.

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("LIQ861 Inhaled Treprostinil")
n      <- c(121)
events <- c(121)
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  LIQ861 Inhaled Treprostinil  121  121  100.0  97.0  100.0  96.9  100.0  97.0  100.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure, focused on treatment-emergent adverse events and serious adverse events. It does not report a multiplicity strategy, such as how statistical error would be handled across event categories, dose levels, time points, or other analyses. No inferential analyses are listed. The record also does not report a hierarchy of hypotheses or identify any confirmatory secondary endpoints. Since the posted result is descriptive, a multiplicity-adjusted interpretation cannot be reconstructed from the available registry information.

The stated safety population includes all subjects who received at least 1 inhalation of LIQ861. That definition clarifies who is intended to contribute to the safety summaries. The adverse-event description says there were two treatment arms analyzed for events and that all subjects who participated in the PK study were part of the transition group and were not analyzed separately for adverse events. The registry does not provide a fuller account of how participants were assigned to these analysis groups or how the safety population was handled after treatment interruption or discontinuation.

Missing-data handling is not reported in the registry record. There is no description of how incomplete adverse-event reporting, missed visits, withdrawal, or loss to follow-up affected the counts. The stated schedule extends through bimonthly follow-up for up to 16 months, but the record does not provide individual follow-up completeness or reasons for missing observations. It is therefore not possible to assess whether the posted counts represent complete observation for all participants or to determine the direction of any bias from missing information.

Details of the statistical analysis plan, including any interim analyses, are not reported in the registry record. Those omissions matter because event summaries can depend on outcome definitions, exposure time, follow-up completeness, and choices about how to handle multiple categories. The registry entries support a descriptive reading, but they do not permit a full audit of analysis decisions or a reconstruction of unreported analyses.

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: pneumonia (1.7%), dyspnoea (1.7%), syncope (1.7%), pulmonary embolism (1.7%), acute respiratory failure (0.8%).

The LIQ861 Add-On group has 15 participants listed with serious adverse events and 66 with other adverse events. The Tyvaso Transition group has 6 participants listed with serious adverse events and 55 with other adverse events. Each group’s listed at-risk count is 121 for both categories. These entries are counts of participants, not counts of event episodes.

The serious-event terms reported most frequently are pneumonia, dyspnoea, syncope, and pulmonary embolism, each at 1.7%. Acute respiratory failure and cardiac failure are each reported at 0.8%. The registry does not give participant counts alongside these term-level percentages in this listing. It also does not say whether a participant could appear under more than one term, so the percentages should not be added together or read as mutually exclusive shares.

Zero deaths are listed for each group. These entries describe the posted results and do not establish that the study could exclude uncommon outcomes. The counts are not adjusted for observation time, and the registry does not report event timing or individual follow-up completeness. Because the groups were not randomized, the figures should not be read as a controlled comparison of treatment-related risk.

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

The results establish that the registry recorded adverse-event counts for the LIQ861 Add-On and Tyvaso Transition groups, including counts for serious and other adverse events. They also identify several serious-event terms and list zero deaths in each group. This information contributes to a descriptive account of what was observed during a study whose primary objective was long-term safety and tolerability.

The results do not establish that LIQ861 caused or prevented any listed event. The study is open-label, allocation is NA, and the registry explicitly cautions that the groups are not a like-for-like control comparison. Differences in the posted counts cannot be treated as causal treatment effects. Group membership, prior treatment, participant characteristics, and exposure duration may influence descriptive counts, but those details are not reported in the registry record.

The counts also do not tell how often each event episode occurred, how long events lasted, or how severe events were beyond the serious classification. The participant-count endpoint does not express the number of episodes per person or adjust for time at risk. Although the record gives a follow-up schedule extending for up to 16 months, it does not report the observed follow-up duration for each participant. Nor does it provide a confidence interval or other measure of statistical precision for the posted counts.

Term-level percentages should be interpreted as registry-reported summaries, not as a complete accounting of all possible safety outcomes. The record does not provide enough detail to determine overlap across terms, to assess whether all categories were prespecified, or to evaluate missing event information. It does not report a comparative statistical model, adjustment for baseline differences, or multiplicity procedures.

In short, these data describe adverse events recorded in the study’s safety population and its named groups. They do not, on their own, quantify comparative risk, demonstrate causation, or show how the results would apply to people outside the registry’s described population. Those questions require design and analysis details that are not reported in the registry record.

14. Why This Trial Matters Statistically

Safety studies often produce information that is important to clinical researchers even when they are not designed to estimate a randomized treatment contrast. This study’s stated objective was to evaluate long-term safety and tolerability of inhaled LIQ861 in patients with PAH. Reporting participant counts for serious and other adverse events makes the registry record useful for understanding the kinds of safety summaries collected during that objective.

The study also illustrates why design labels and analysis populations matter. The adverse-event results name LIQ861 Add-On and Tyvaso Transition groups, but the record describes a single-group model, open-label masking, and allocation listed as NA. Recognizing that these are not randomized, like-for-like controls prevents descriptive group differences from being mistaken for comparative evidence. The transition group’s inclusion of participants in the PK study, who were not analyzed separately for adverse events, is another detail relevant to interpreting the grouping.

From a statistical perspective, the endpoint is a participant count, while follow-up extends over a schedule that can span up to 16 months. This highlights a general distinction between counting people with events and estimating time-adjusted rates. Without individual follow-up duration, event timing, or a reported time-to-event analysis, readers should avoid interpreting counts as rates.

The registry’s limits are also instructive. It records selected safety results but does not report confidence intervals, an inferential model, missing-data procedures, or multiplicity handling. Transparent reporting of such details helps readers assess precision and the scope of conclusions. The posted information supports a focused descriptive reading, while leaving important questions about comparative inference and data completeness unanswered.

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 is the absence of a randomized, like-for-like comparator. The registry identifies the study as open-label, lists allocation as NA, and classifies its model as single-group. Although results are presented for LIQ861 Add-On and Tyvaso Transition, the registry itself cautions against treating them as a control comparison. Differences in group counts therefore cannot be interpreted as treatment effects.

The endpoint is a count of participants with events, not a rate adjusted for time at risk. The scheduled follow-up includes visits from baseline through Month 2 and bimonthly follow-up for up to 16 months, but individual observation times and follow-up completeness are not reported. The record does not state how events after treatment changes, interruptions, or discontinuation were handled, or how missing safety information affected the summaries.

Although the registry says events were to be grouped by MedDRA System Organ Class, dose level, time on drug, and relationship to dose titration, it does not report a complete breakdown across those dimensions. The listed serious-event terms do not include participant counts in the term listing, and overlap among terms is not described. No inferential estimates, confidence intervals, statistical model, or adjustment for group differences are reported.

Finally, the record does not report detailed participant characteristics, group-entry procedures, or treatment exposure histories. These gaps limit assessment of the context behind the counts and the extent to which the observed summaries reflect differences in exposure or population composition. The results are consequently best treated as registry-level descriptive safety information, rather than a comprehensive or comparative assessment of risk.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil — NCT03399604.
• Registry record last updated 2024-07-30; status last verified 2024-07.
• Results first posted 2024-07-30.
• 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

NCT03399604 is a completed Phase 3, open-label, multicenter study sponsored by Liquidia Technologies, Inc. Its official title describes long-term safety and tolerability evaluation of inhaled LIQ861 treprostinil in patients with PAH, WHO Group 1. The registry lists enrollment of 121, a start date of 2018-01-02, and a primary completion date of 2019-05-06.

The primary objective was safety and tolerability. The registry reports serious and other adverse-event participant counts for LIQ861 Add-On and Tyvaso Transition, along with selected serious-event terms and death counts. It identifies the safety population as participants who received at least 1 inhalation of LIQ861. The group labels do not define randomized controls; the record lists allocation as NA and explicitly warns that the groups are not a like-for-like comparison.

The posted counts are descriptive. The registry does not report inferential analyses, confidence intervals, missing-data methods, or a comparative statistical model. Accordingly, the record supports a summary of reported safety events but not a causal comparison between groups.