A Study of RPL554 Drug Administered by Metered Dose Inhaler to Treat Chronic Obstructive Pulmonary Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of RPL554 Drug Administered by Metered Dose Inhaler to Treat Chronic Obstructive Pulmonary Disease (NCT04091360), a randomized phase 2 study. The primary outcome is Part A: Pharmacokinetic Parameter AUC0-12.

2. Clinical Question

3. Trial Design

This was a Phase II, randomized, double-blind, crossover study of RPL554 administered by pressurized metered dose inhaler in patients with COPD. The registry lists an enrollment of 40 and records the study as completed. The recorded start date is 2019-04-29 and the primary completion date is 2020-12-10.

The study had two parts. Part A evaluated single doses of RPL554 across five dose groups, with an additional placebo group. The posted primary endpoint is the Day 1 pharmacokinetic measure following a single dose. The primary analysis set was defined by post-dose blood sampling and evaluable pharmacokinetic data among participants who received RPL554; the 7 placebo participants were excluded from that set.

Part B assessed repeat doses in a crossover design. The registry describes repeat-dose assessments for RPL554 and placebo and posts Day 7 lung-function outcomes. In a crossover study, participants receive more than one assigned condition in sequence, so comparisons can use within-participant information. General considerations for crossover analyses include accounting for treatment sequence, period, and possible carryover. Which specific terms or adjustments were used for each posted analysis is not reported in the registry record.

Although the registry identifies randomization and double masking, details such as the randomization procedure, allocation concealment, masking procedures, washout periods, and the precise crossover sequence are not reported in the registry record. A protocol-level statistical analysis plan and the rationale for the enrollment target are also 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: Part A: 40 Patients randomized equally to receive a single dose of RPL554 (0.10, 0.30, 1, 3, or 6 mg) or matching placebo via pressurized metered dose inhaler (pMDI). Patients continued to Part B after Part A completed. Part B: 28 Patients continued to Part B and randomly assigned to 1 of 4 treatment sequences in a crossover design (1-week treatment periods separated by 7-10 day washout). Each sequence included twice daily RPL554 (0.30, 1, or 3 mg) or matching placebo via pMDI.

Only the first 6 of 10 groups are shown.

Part A (R, PC, PG) Single Dose

Part B (R, PC, XO) Twice Daily for 7 Day

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) Analysis Set in Part A: all randomized patients who had blood sampling performed after the single dose of RPL554 and had evaluable PK parameter data. The PK Analysis Set included the 33 patients who received RPL554 in Part A but not the 7 patients in the placebo group.

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Pharmacokinetic Parameter AUC0-12, measured over Day 1.

The primary endpoint is Part A pharmacokinetic parameter AUC0-12 on Day 1, reported as a mean with standard deviation in h*pg/mL. It represents the area under the drug concentration-time curve from 0 to 12 hours after a single dose of RPL554. In general, an area-under-the-curve measure summarizes exposure across a defined time interval: it reflects both the concentration observed and how those concentrations evolve during that interval.

This type of endpoint is used in pharmacokinetic studies to characterize systemic drug exposure across doses. Comparing the reported means across dose groups can describe how observed exposure varies with the administered dose. The standard deviation gives an indication of the spread of individual measurements around each group mean; it is not a confidence interval for the mean.

The endpoint does not itself measure symptoms, daily functioning, or a clinical outcome. Nor does a larger mean exposure, by itself, establish a clinical effect. The registry record does not post a placebo-based primary endpoint comparison, confidence intervals for the primary group means, or an inferential analysis of the relationship between dose and exposure. The posted primary data therefore describe the pharmacokinetic observations in the RPL554 analysis set rather than a definitive test of a dose effect or treatment benefit.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish the observed data from the uncertainty and assumptions attached to an estimate. The primary result is a continuous measure: the mean AUC0-12 for each RPL554 dose group. A mean is the arithmetic average of the observed endpoint values in a group. The standard deviation summarizes how dispersed those values are around the mean. General explanation: a larger standard deviation indicates more variability among individuals, but does not by itself show whether the group mean is precisely estimated. Precision also depends on the number of observations and the distribution of the data.

What does the primary endpoint estimate?

The primary endpoint is an exposure summary over the interval from 0 to 12 hours after a single dose. It is posted separately for each RPL554 dose group, with no primary comparison estimate, confidence interval, or p-value. As a result, the dose-specific means describe the observed pharmacokinetic pattern, but the registry does not provide a formal test of differences between dose groups. The placebo participants are not included in the primary analysis set because the endpoint population is defined as RPL554 recipients with evaluable pharmacokinetic data.

How should confidence intervals be read?

General explanation: a confidence interval gives a range of values compatible with an estimate under a specified statistical procedure and its assumptions. A narrow interval indicates greater precision than a wide interval on the same scale. For the Part B recalculated mean differences, the interval is expressed in liters and describes uncertainty around the difference in group means. If such an interval includes zero, the data are compatible with no difference under that unadjusted method as well as with values on either side of zero. The sponsor-reported ANCOVA estimates are geometric mean ratios, for which the relevant neutral value is a ratio of one; these analyses should be interpreted on their own scale.

The primary means have no posted confidence intervals. The standard deviations beside those means are measures of observed variability, not substitutes for confidence intervals. A reader should not infer formal statistical significance from the ordering of the means alone.

What is the distinction between posted and recalculated analyses?

The recalculated Part B comparisons use unadjusted summaries of the group means and standard deviations. They provide a simple comparison of the posted group data and are not the same as a model-based analysis. The sponsor-reported analyses use ANCOVA and report geometric mean ratios. In general, ANCOVA is a regression approach that can estimate a group contrast while accounting for specified covariates. The registry record does not identify the covariates, model specification, or all analysis details for these ANCOVA results. The sponsor's own analysis takes precedence over a simple unadjusted recalculation for the sponsor-reported comparison.

The study's crossover structure also matters. General explanation: crossover designs can control for stable differences between participants because participants receive multiple conditions. Valid analysis may also need to account for treatment sequence and period, and to consider carryover from earlier treatment periods. The registry record does not report enough detail to establish how those design features were handled in each analysis. The posted Part B group summaries should therefore not be assumed to represent a particular paired or crossover-adjusted estimator unless the analysis explicitly says so.

What do the planning illustrations mean?

Planning illustrations use the observed effect as an assumed target for a hypothetical future study. The posted assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation, with alternative targets defined as fractions of the observed effect. These calculations are not the original study's design justification, are not observed power, and do not show that a future study would achieve the stated power. They depend on the assumed effect and the statistical assumptions. The registry record does not report the original sample-size justification.

For continuous outcomes, such illustrations express participants per arm for a selected power and assumed effect. Smaller assumed effects generally require larger planned samples under the same assumptions. These figures are best used to show how strongly a sample-size estimate depends on the effect chosen, not as a retrospective verdict on whether the completed study was adequately powered. No such planning calculation changes the uncertainty around the actual observed estimates.

Why can multiplicity affect interpretation?

General explanation: when many outcomes or comparisons are tested, the chance of at least one apparently small p-value can increase, even if none of the tested effects is real. Multiplicity procedures can control this issue, but the registry record does not report whether a prespecified adjustment was planned or applied to the posted secondary comparisons. The displayed unadjusted p-values therefore do not establish confirmatory evidence across the full set of outcomes.

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("0.10 mg", "0.30 mg", "1 mg", "3 mg", "6 mg")
n   <- c(6, 7, 6, 7, 7)
m   <- c(175, 611, 1550, 5860, 9360)
sp  <- c(96.7, 183, 443, 3120, 8100)
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  0.10 mg  6  175.000  96.700  73.520  276.480
CARM  0.30 mg  7  611.000  183.000  441.753  780.247
CARM  1 mg  6  1550.000  443.000  1085.100  2014.900
CARM  3 mg  7  5860.000  3120.000  2974.481  8745.519
CARM  6 mg  7  9360.000  8100.000  1868.749  16851.251

11. Multiplicity, Missing Data and Analysis Populations

The registry posts a primary pharmacokinetic endpoint alongside a broad set of secondary outcome measures and analyses. It reports 29 outcome measures and 36 analyses overall, with 24 secondary outcomes posted. The record does not report a prespecified testing hierarchy, family-wise error procedure, false-discovery procedure, or other multiplicity adjustment for the secondary comparisons. Accordingly, the posted secondary p-values should be understood as unadjusted unless an analysis is explicitly described otherwise.

General explanation: multiplicity arises when several hypotheses are tested. Without adjustment or a clearly prespecified hierarchy, the chance of at least one small p-value arising by chance increases as the number of tests grows. This does not mean that every observed association is spurious; it means that isolated results need more cautious interpretation and preferably independent confirmation. The available record does not establish which secondary outcomes were intended as confirmatory.

The primary analysis population is described as randomized participants who had blood sampling after the single dose and evaluable pharmacokinetic data. It includes 33 participants who received RPL554 in Part A and excludes the 7 placebo participants. This is an endpoint-specific analysis set, rather than all 40 enrolled participants. The registry record does not report the number screened, the number randomized by sequence, reasons for exclusion or missing measurements, or a detailed participant flow for the analyses.

Missing-data procedures, the handling of incomplete pharmacokinetic profiles, and sensitivity analyses are not reported in the registry record. For Part B, the information needed to assess missing outcome data and the exact analysis population is also not reported in the registry record. The record does not state whether analyses followed an intention-to-treat principle, how any withdrawals were handled, or whether imputation was used. These omissions limit assessment of how representative the analyzed participants are of everyone randomized and how robust the results are to missing observations.

The sample-size planning illustrations are based on observed effects and specified assumptions, not on the original study design. The registry record does not report the study's own sample-size justification or planned power calculation. It also does not report an interim-analysis plan.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The posted serious adverse event figures show zero participants with a serious adverse event in every listed Part A and Part B group. The death count is also zero in every listed group. The numbers at risk differ across groups and parts of the study, so each count should be interpreted with its corresponding group size rather than as if all groups contributed the same observation time or exposure.

These figures describe what was recorded in the registry for the listed groups. They do not establish that a serious event is impossible, and a zero count in a small study cannot rule out uncommon events. General explanation: safety estimates are imprecise when the number of exposed participants is limited, particularly for rare outcomes. The registry record does not provide confidence intervals for these serious-event counts or detailed event narratives.

The record also lists other adverse events affecting participants in several groups. Those events are distinct from serious adverse events and should not be conflated with the serious-event count. The registry's posted safety information does not by itself establish comparative safety across doses, especially because group sizes are small and Part B uses a crossover design. The study's safety observations are descriptive; they should not be read as a comprehensive estimate of risks outside the trial.

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

The results describe a small Phase II study that assessed single-dose RPL554 pharmacokinetic exposure and included lung-function and safety outcomes. The primary endpoint means increase across the listed single-dose groups, indicating that the observed concentration-time exposure was higher in groups assigned to higher doses. The standard deviations also show variability among participants, particularly in the higher-dose groups.

This finding is about drug exposure over a defined interval. It does not, by itself, establish that participants experienced a meaningful improvement in COPD symptoms, daily functioning, or long-term outcomes. Nor does it show that any dose is optimal. The primary endpoint analysis does not include a placebo comparison or a formal inferential comparison between doses in the registry results.

The secondary lung-function results add observations after repeat dosing, but they are not the same endpoint or analysis population as the primary pharmacokinetic measure. The crossover design and the absence of detailed analysis specifications make it difficult to assess all assumptions underlying those comparisons. Since multiplicity adjustment is not reported, the secondary results should be regarded as exploratory rather than definitive.

The serious adverse event and death counts are zero in the listed groups. That is a description of the events recorded among the participants represented in those groups; it does not rule out uncommon adverse events or establish safety in a broader population. The study size and follow-up information available in the registry limit what can be concluded about rare or longer-term outcomes.

Overall, the posted results characterize pharmacokinetic exposure and provide secondary clinical measurements in a randomized study. They do not independently establish clinical benefit, long-term effectiveness, or a complete safety profile. Details not reported in the registry record—such as the full statistical analysis plan, missing-data handling, and multiplicity strategy—also constrain how confidently the secondary comparisons can be interpreted.

14. Why This Trial Matters Statistically

This trial is statistically interesting because it places a pharmacokinetic dose-ranging question alongside clinical measurements in a randomized crossover study. The primary endpoint focuses on the concentration-time exposure after a single dose, while Part B adds repeat-dose lung-function observations. Keeping these questions distinct is essential: an exposure pattern and a clinical outcome are related types of evidence, but they are not interchangeable estimands.

The primary results show increasing mean exposure across the listed dose groups, while the standard deviations indicate substantial variability in some groups. That combination illustrates why group means alone do not convey the precision of a dose comparison. With no primary confidence intervals or formal comparison estimates posted, the registry supports a descriptive reading of the dose groups rather than a quantified inferential claim.

The study also illustrates how design affects analysis. A crossover structure can make within-participant comparisons useful, but interpretation depends on how period, sequence, and possible carryover are handled. Those details are not reported in the registry record, so the estimates cannot be fully evaluated from the posted descriptions alone.

Finally, the number of posted endpoints and analyses makes multiplicity relevant. Secondary comparisons can be informative, but unadjusted p-values across many outcomes are not equivalent to a single prespecified confirmatory test. The record's missing detail about multiplicity and missing-data methods is therefore an important part of statistical interpretation, not a minor reporting issue. This study provides useful descriptive information about exposure and selected outcomes while also showing why the analysis plan and uncertainty estimates matter.

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.

Several trial-specific limitations constrain interpretation. The primary endpoint is reported as dose-group means and standard deviations, without confidence intervals or a formal comparison among dose groups. The increasing means are descriptive; the registry does not provide a primary inferential estimate of the dose-response relationship. The placebo participants are excluded from the primary pharmacokinetic analysis set, so the primary result is not a placebo-controlled endpoint comparison.

The analysis set includes 33 RPL554 recipients with evaluable pharmacokinetic data, rather than all 40 enrolled participants. Reasons for missing or unevaluable data, participant flow, and sensitivity analyses are not reported in the registry record. The exact analysis populations for the posted Part B outcomes and handling of missing repeated measurements are also not reported in the registry record.

The Part B comparisons involve relatively small groups. This limits precision and makes the estimates potentially sensitive to individual observations. The study's crossover design makes period, sequence, and carryover considerations relevant, but the statistical handling of those features is not reported in the registry record. The covariates and model specifications for the sponsor-reported ANCOVA analyses are likewise not reported in the registry record.

Many outcomes and analyses are posted, but a multiplicity strategy or hierarchy is not reported in the registry record. The secondary p-values therefore have to be read cautiously. The record also does not report the original sample-size justification, interim analyses, or a complete statistical analysis plan. Finally, the listed safety counts are descriptive and based on the study groups; they cannot resolve the frequency of uncommon events or establish long-term safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of RPL554 Drug Administered by Metered Dose Inhaler to Treat Chronic Obstructive Pulmonary Disease — NCT04091360.
• Registry record last updated 2022-09-21; status last verified 2022-08.
• Results first posted 2022-07-25.
• 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

NCT04091360 is a completed Phase II randomized, double-blind crossover study of RPL554 administered by pressurized metered dose inhaler in patients with COPD. The registry lists an enrollment of 40, a start date of 2019-04-29, and a primary completion date of 2020-12-10.

The primary endpoint is Part A AUC0-12 on Day 1, a pharmacokinetic measure of exposure after a single dose. The analysis set included 33 RPL554 recipients with evaluable pharmacokinetic data and excluded the 7 placebo participants. The posted mean exposure values rise across the listed RPL554 dose groups, with substantial variability in some groups.

Part B posts repeat-dose lung-function outcomes and selected comparisons. The registry also records zero serious adverse events and zero deaths in each listed group. Multiplicity procedures, detailed missing-data methods, crossover model specifications, and the original sample-size rationale are not reported in the registry record, limiting the strength of conclusions that can be drawn from secondary analyses.