Inhaled Imatinib Pulmonary Arterial Hypertension Clinical Trial - Follow Up Long Term Extension (IMPAHCT-FUL): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Inhaled Imatinib Pulmonary Arterial Hypertension Clinical Trial - Follow Up Long Term Extension (IMPAHCT-FUL) (NCT05557942), a randomized phase 3 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events.

2. Clinical Question

The registry lists a randomized, quadruple-masked, parallel-group, Phase 3 study. It does not report enough allocation detail to explain how those design labels relate to the groups defined by treatment received in the parent study. In particular, the record does not say whether participants were newly randomized among the extension doses or how assignment to the listed groups was carried out.

3. Trial Design

IMPAHCT-FUL was a long-term extension study intended to establish the long-term safety of AV-101 in participants with pulmonary arterial hypertension who had completed the parent study, AV-101-002. Participants who successfully completed that 24-week placebo-controlled study were offered the opportunity to enroll. The registry describes three active AV-101 doses and six groups organized by both extension dose and prior treatment history: participants who crossed over from placebo and participants who continued AV-101 received 10 mg, 35 mg, or 70 mg twice daily by dry powder inhalation.

The study is listed as randomized, quadruple-masked, parallel-group, and Phase 3. The official title describes it as a multi-center safety study. The registry does not report the method of randomization, masking roles, allocation ratio, stratification, or whether the extension assignment itself was randomized. It also does not state the rationale for the number of participants or the original sample-size assumptions. Those details should not be inferred from the design labels alone.

The record lists enrollment of 186 and a study status of terminated. The start date is 2022-11-02, and the primary completion date is 2024-08-08. The reason for termination and its implications for follow-up are not reported in the registry record. The brief summary says that participants were to receive one of three active doses until the optimal dose was selected in the parent study; it does not explain how that selection was made or what dose was selected.

The posted primary measure is a safety count, not a comparison of clinical benefit. No secondary outcomes are posted, and no analyses are listed in the registry record. The group counts therefore describe the participants reported for the safety outcome; they should not be treated as a complete account of every planned analysis or of outcomes not posted.

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:

Analysis population for the primary outcome, as defined in the registry: The Safety Analysis Set included all participants that received at least one dose of study drug.

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: The Intent-to-treat (ITT) analysis set included all randomized participants.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events, measured over From date of first dose to 30 days after date of last dose (up to approximately 21 months).

The primary endpoint is the number of participants with treatment-emergent adverse events. An adverse event was defined as any untoward medical occurrence in a participant who received study drug, regardless of whether it was considered causally related to the drug. The endpoint timeframe runs from the first dose through 30 days after the last dose, for up to approximately 21 months.

The registry distinguishes serious adverse events using specified seriousness criteria, including death, a life-threatening event, inpatient hospitalization or prolongation of hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event requiring intervention to prevent one of those outcomes. The primary endpoint, however, is the number of participants with treatment-emergent adverse events; the registry directs readers to its reported adverse-event information for summaries of serious and other non-serious events.

Counting participants with an event is a way to describe how many people experienced at least one event during the defined safety window. It is not the same as counting every event: one participant can experience more than one adverse event. As a general statistical point, this participant-level summary is useful for describing the proportion of a safety population affected, but it does not by itself characterize event duration, recurrence, severity beyond the reported classifications, or causal attribution. The registry’s definition explicitly does not require a causal relationship.

7. Results Posted in the Registry

• Placebo Crossover AV-101 35 mg: 61.1% (11/18) versus 50.0% (9/18) on control; risk difference 11.1 percentage points (95% CI -21.1 to 43.4), risk ratio 1.22 (0.68–2.21); unadjusted two-proportion z-test p = 0.502.
• Placebo Crossover AV-101 70 mg: 75.0% (12/16) versus 50.0% (9/18) on control; risk difference 25.0 percentage points (95% CI -6.4 to 56.4), risk ratio 1.50 (0.87–2.58); unadjusted two-proportion z-test p = 0.134.
• Continuing AV-101 10 mg: 57.8% (26/45) versus 50.0% (9/18) on control; risk difference 7.8 percentage points (95% CI -19.5 to 35.0), risk ratio 1.16 (0.68–1.95); unadjusted two-proportion z-test p = 0.575.
• Continuing AV-101 35 mg: 52.1% (25/48) versus 50.0% (9/18) on control; risk difference 2.1 percentage points (95% CI -25.0 to 29.2), risk ratio 1.04 (0.61–1.78); unadjusted two-proportion z-test p = 0.880.

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is binary at the participant level: a participant either had at least one treatment-emergent adverse event during the stated safety window or did not. The registry reports the number of affected participants and the number in each group’s safety set. This is distinct from an event-level analysis, which would count repeated events experienced by the same person. A participant with several events still contributes once to a participant-count outcome.

The comparison measure reported in the recalculations is the risk difference. It expresses the difference between the observed proportions with an event in the compared group and the reference group. A value above zero indicates a higher observed proportion in the compared group; a value below zero indicates a lower observed proportion. Zero represents no difference in the observed proportions. The listed estimates are unadjusted and use Placebo Crossover AV-101 10 mg as the reference. Because this reference group received AV-101 during the extension, its name should not be read as indicating a concurrent placebo control.

Confidence intervals describe uncertainty around an estimated difference. In general, a confidence interval is a range of values compatible with the data under the calculation’s assumptions; it is not a guarantee that the true value lies in the interval. An interval that includes zero does not rule out meaningful differences in either direction, especially when the interval is broad. The intervals in these comparisons all include zero and extend across both negative and positive values. That pattern reflects limited precision in the posted group summaries rather than proof that the groups are identical.

The record also gives relative risks and odds ratios for the comparisons. These are alternative ways to express the relationship between group event proportions. A relative risk compares the event proportion in one group with that in the reference; an odds ratio compares the groups’ event odds. They can be less intuitive than a risk difference, and for a rare outcome they may be numerically similar while for common outcomes they need not be. General statistical point: relative measures do not replace the underlying counts, and their interpretation still depends on the comparison groups and study design. The registry does not report adjusted analyses, so the listed measures should not be interpreted as controlling for other characteristics.

The p-values are labeled unadjusted. In general, a p-value quantifies how incompatible the observed data are with a specified null model, assuming that model and the analysis assumptions are appropriate. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. The record does not report a sponsor analysis for this outcome or a detailed statistical analysis plan. These comparisons are recalculations from the posted summary counts, rather than a replacement for a prespecified sponsor analysis. The registry does not report whether or how multiplicity was addressed across the several comparisons.

The six groups are defined by dose and prior treatment history. Participants in the crossover groups had received placebo in the parent study and then received active AV-101 in the extension. Participants in the continuing groups had received AV-101 in the parent study and continued AV-101. As a general design principle, prior treatment and selection into an extension can affect how groups compare. The registry record does not provide enough detail about allocation, baseline comparability, or adjustment to determine whether those issues were addressed analytically. It also does not state whether the extension dose assignment was randomized despite listing the study as randomized.

The primary population is the Safety Analysis Set, defined as participants who received at least one dose of study drug. This is a safety population rather than necessarily the same population used for every possible efficacy analysis. No efficacy outcome or secondary outcome is posted, and the registry record does not describe how missing safety follow-up was handled. General statistical point: excluding participants with incomplete follow-up or treating them as event-free can change an estimated event proportion, so missing-data rules matter. No such rule should be assumed for this study.

The registry’s serious adverse-event definition classifies events by seriousness criteria, not by whether the study drug caused them. The primary adverse-event definition also includes events regardless of causal relationship. Therefore, the counts describe observed safety events during the study window and do not by themselves establish drug attribution. The registry does not report a comparative causal analysis of adverse events or a method for adjudicating causality. The reported summaries should be read as descriptive safety findings, alongside the study’s design and follow-up limitations.

10. Confidence Intervals and Precision

Precision is limited for these comparisons. The risk-difference intervals are broad relative to their point estimates, and each interval includes zero. For Placebo Crossover AV-101 35 mg, the estimate is 0.111 and the interval is -0.211 to 0.434. For Placebo Crossover AV-101 70 mg, the estimate is 0.25 and the interval is -0.064 to 0.564. The corresponding unadjusted p-values are 0.502 and 0.134.

For Continuing AV-101 10 mg, the estimate is 0.078, with an interval from -0.195 to 0.350. For Continuing AV-101 35 mg, the estimate is 0.021, with an interval from -0.25 to 0.292. For Continuing AV-101 70 mg, the estimate is 0.012, with an interval from -0.265 to 0.289. Their unadjusted p-values are 0.575, 0.88, and 0.931, respectively.

In general, a wider confidence interval indicates greater uncertainty about the magnitude and direction of an estimated effect. Here, the intervals allow both lower and higher event proportions relative to the reference. The posted counts also show that the reference group contains 18 participants, while the compared groups contain 16, 18, 45, 48, or 41 participants. Such group sizes offer limited information for estimating differences precisely, particularly when events are common in the observed groups. The estimates should not be read as proof of no difference, nor as precise estimates of a dose-related pattern.

These intervals represent uncertainty in unadjusted recalculations from the posted summary data. The registry record does not report a sponsor-generated confidence interval analysis, an adjustment strategy, or a prespecified statistical model for these comparisons. Precision therefore describes what can be inferred from the posted summaries, not a full assessment of the study’s planned analysis.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning illustrations express sample size as participants per arm, not total events. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The assumed effect to detect is a stated fraction of the observed effect. These are planning assumptions for the illustrations; the registry record does not report the trial’s original sample-size justification or design assumptions.

The 80% power column gives the number of participants per arm that the illustration estimates would be needed for an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding number per arm for a higher chance of detection. These values are planning scenarios, not the observed enrollment in the six extension groups. Smaller assumed effects require more participants because a smaller difference is harder to distinguish from random variation.

The effect fractions are tied to the observed risk differences in small groups, so the resulting planning values can be especially sensitive to the estimated effect. For example, the illustrations for Continuing AV-101 35 mg and Continuing AV-101 70 mg yield very large per-arm requirements when using their observed effects. That should not be read as an appropriate definitive-trial target: it reflects a calculation based on the observed summaries and the stated assumptions, not an independently justified design proposal. These figures are not observed power.

The registry record does not state that these illustrations were the basis for IMPAHCT-FUL’s design. They do not account for any unreported features such as missing follow-up, multiplicity, differences in treatment history, or a different analysis model. They should be interpreted only as conditional planning examples for two-arm comparisons under the stated assumptions.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.500; treatment proportion p₁ = 0.611; average p̄ = 0.556.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7027 = 1.3773.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6983 = 0.5877.
4. n = (1.3773 + 0.5877)² / (0.1111)² = 312.8, rounded up to 313 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.5                          # control proportion
p1 <- 0.611111111111111                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(5557942)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 313 (80% power), 419 (90% power)
 75% of observed effect: n per arm = 561 (80% power), 750 (90% power)
 50% of observed effect: n per arm = 1,267 (80% power), 1,695 (90% power)
power.prop.test: 312.8 
Simulated power at n = 313 per arm: 0.795 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The recalculated results compare five groups with the Placebo Crossover AV-101 10 mg reference. Each comparison has an unadjusted p-value. The registry record does not report a multiplicity correction or a prespecified strategy for interpreting several comparisons together. When multiple hypotheses are tested, the chance of at least one apparently unusual result can increase; as a general statistical point, adjustment or a clearly prespecified interpretation strategy can address that issue. No such approach should be presumed for these results.

Missing-data handling is not reported in the registry record. The outcome timeframe extends from first dose through 30 days after last dose, for up to approximately 21 months, but the record does not describe how participants with incomplete follow-up were handled or how exposure duration affected the summary. The posted participant counts should therefore be interpreted in light of an undocumented missing-data approach rather than assuming that all participants had identical observation time.

The primary population is defined as the Safety Analysis Set, including participants who received at least one dose of study drug. The record does not describe other analysis populations, exclusions, or population-specific sensitivity analyses. It lists the study as randomized but does not report the extension allocation procedure or explain whether the posted groups correspond to a randomized allocation. No analysis is listed in the registry record, and no secondary outcomes are posted.

These omissions limit assessment of whether the reported comparisons follow an analysis plan, whether incomplete data could have affected the findings, and how to interpret the multiple unadjusted comparisons. They do not change the descriptive counts, but they constrain inferential conclusions based on them.

14. 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 (6.7%), influenza (6.2%), gastroenteritis (6.2%), acute sinusitis (6.2%), atypical pneumonia (6.2%).

The serious adverse-event summaries report participants at risk and participants affected in each group. The figures are 3 of 18 in Placebo Crossover AV-101 10 mg, 4 of 18 in Placebo Crossover AV-101 35 mg, and 6 of 16 in Placebo Crossover AV-101 70 mg. Among participants continuing AV-101, the serious adverse-event counts are 12 of 45 at 10 mg, 9 of 48 at 35 mg, and 7 of 41 at 70 mg. The reported deaths are 0, 0, 0, 2, 1, and 1 in those same group orderings.

These are descriptive participant counts, not evidence that a treatment caused an event. The registry defines adverse events without requiring a causal relationship to study drug, and the serious-event definition is based on seriousness criteria. Participants may have experienced more than one event, so participant counts are not necessarily counts of all event episodes.

The listed serious-event terms include Right ventricular failure at 6.7%, and Influenza, Gastroenteritis, Acute sinusitis, Atypical pneumonia, and Vascular device infection, each at 6.2%. The record does not attach these term percentages to a specific dose-group comparison in the information. They should not be treated as a causal ranking or as estimates of comparative risk. Group differences in these descriptive counts do not establish that dose explains the pattern.

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

The results describe adverse events reported among participants who received at least one dose of study drug during a long-term extension. The primary measure counts participants with at least one treatment-emergent adverse event, and the record also reports serious-event counts and deaths by group. These observations provide a safety description for the study population and follow-up period recorded by the registry.

The comparisons do not show a precise separation between the listed extension groups. All recalculated risk-difference confidence intervals include zero, and the comparisons are unadjusted. This does not establish that the groups have the same safety experience; the intervals allow differences in either direction. Nor do the comparisons establish that a dose caused a difference. The reference group received active AV-101 during the extension, and the groups differ in both dose and previous treatment history.

The endpoint is not a measure of efficacy, symptom improvement, or disease progression. No efficacy outcome is posted in the registry record, and no secondary outcomes are listed. The study’s stated focus is long-term safety. The adverse-event definition does not require a causal relationship to study drug, so event counts cannot alone determine whether an event was caused by treatment.

The registry status is terminated, but the reason for termination is not reported in the registry record. The record also does not explain how termination affected follow-up or analyses. For those reasons, the posted findings support a descriptive account of observed events and cautious interpretation of the recalculated comparisons, not a broad conclusion about treatment benefit, harm, or comparative safety beyond the recorded data.

16. Why This Trial Matters Statistically

This study illustrates a recurring statistical challenge in long-term extension research: safety observations accumulate after a placebo-controlled parent study, but the extension groups may no longer provide a concurrent untreated comparison. In IMPAHCT-FUL, participants who previously received placebo crossed over to active AV-101, while other participants continued active treatment. The extension comparisons therefore combine dose and treatment history, making the interpretation different from a simple randomized active-versus-placebo contrast.

It also shows why counts, effect estimates, and uncertainty need to be read together. The participant counts describe observed events, while risk differences express the contrast with a reference group. The confidence intervals are broad and include zero for every listed comparison. The point estimates alone could suggest a direction, but they do not establish a reliable dose pattern or causal effect.

The registry’s missing analysis-plan details matter statistically. The record lists a randomized design but does not explain how extension allocation was carried out. It lists unadjusted recalculated comparisons but no sponsor analyses, multiplicity strategy, or missing-data approach. Those gaps limit the strength of inferential claims even when the descriptive safety counts are available.

Finally, the sample-size illustrations show how planning depends on the assumed effect. Calculations based on observed effects can produce very different planning requirements and should not be mistaken for evidence that a study had adequate or inadequate power. The original design justification is not reported in the registry record. Overall, the trial is a useful case for distinguishing safety description, comparative estimation, design assumptions, and what remains uncertain.

17. 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 extension’s comparison structure is an important limitation. The reference group received active AV-101 after placebo crossover, while the continuing groups had prior AV-101 exposure. As a result, the groups differ in treatment history as well as dose. The registry lists randomization but does not report how participants were allocated in the extension, how the listed groups were formed, or whether any baseline differences were accounted for.

The primary outcome is a participant count with an event over a variable follow-up window extending from first dose to 30 days after last dose, for up to approximately 21 months. The record does not report exposure-adjusted event rates, the amount of follow-up by group, or how incomplete safety follow-up was handled. Counts alone cannot describe event timing, recurrence, or the rate at which events accumulated.

The group sizes reported for the comparisons are limited, and the confidence intervals are broad. This reduces the precision of comparisons and leaves substantial uncertainty about their magnitude and direction. The recalculated p-values are unadjusted; a multiplicity strategy is not reported. The registry also lists no sponsor analyses and no secondary outcome measures, so the posted summaries do not provide a broader analysis of efficacy or safety.

The record reports that the study was terminated but does not give the reason or describe its effects on enrollment, follow-up, or analysis. The endpoint definition includes events regardless of causal relationship to study drug, which is appropriate for describing treatment-emergent occurrences but does not establish causation. These limitations restrict interpretation to the registry’s descriptive safety findings and the uncertain unadjusted comparisons.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Inhaled Imatinib Pulmonary Arterial Hypertension Clinical Trial - Follow Up Long Term Extension (IMPAHCT-FUL) — NCT05557942.
• Registry record last updated 2024-10-10; status last verified 2024-10.
• Results first posted 2024-10-10.
• 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.

21. Record Summary

IMPAHCT-FUL (NCT05557942) is a Phase 3, randomized, quadruple-masked, parallel-group long-term extension study of AV-101 in pulmonary arterial hypertension. Participants who completed the 24-week placebo-controlled parent study were offered enrollment and received active AV-101 by twice-daily dry powder inhalation at 10 mg, 35 mg, or 70 mg, either after placebo crossover or as continuation of prior AV-101 treatment.

The registry lists enrollment of 186, a start date of 2022-11-02, a primary completion date of 2024-08-08, and terminated status. The primary outcome counts participants with treatment-emergent adverse events from first dose through 30 days after last dose, for up to approximately 21 months. No secondary outcomes or analyses are listed. The registry does not report the reason for termination, the original sample-size justification, or detailed analysis and missing-data plans.