Frespaciguat (MK-5475) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Frespaciguat (MK-5475) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006) (NCT04370873), a randomized phase 1 study. The primary outcome is Percentage of Participants Who Experienced at Least 1 Adverse Event (AE).

2. Clinical Question

3. Trial Design

This was a randomized, double-masked Phase 1 study, marked as completed, with enrollment of 22 participants. The design is described as sequential. The registry record gives a start date of 2020-06-05 and a primary completion date of 2022-01-12. It does not report the allocation ratio, the randomization procedure, or which people were masked.

The study had two parts with different dosing schemes. In Part 1, participants assigned to frespaciguat received 360 μg by inhalation once daily from Days 1-7. After pharmacokinetic and safety data review, a second 7 days of dosing could be initiated; based on pharmacokinetic data, dosing could be up to 360 μg up to twice a day. The Part 1 placebo group received placebo once daily from Days 1-7. In Part 2, frespaciguat doses were 32 µg, 100 µg, 195 µg or 380 μg once daily by inhalation from Days 1-28, with a Part 2 placebo group dosed once daily for the same stated period.

The primary-outcome results list Part 1 groups receiving 360 μg frespaciguat or placebo and Part 2 groups receiving 380 μg frespaciguat or placebo. The reported group sizes are 6, 3, 9 and 5, respectively. The registry record does not explain the selection of the dose groups included in those primary-outcome results or give a detailed account of the sequence of dose decisions. The study summary names safety and tolerability, pharmacokinetics, and pharmacodynamics as study interests. Secondary outcomes listed include plasma concentration and pharmacokinetic measures for Part 1. Further protocol details and the statistical design rationale 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: There were three planned parts in the study. Participants in part 1 received MK-5475 360 μg. Participants in part 2 received MK-5475 380 μg. Part 3 was not performed because, as allowed by the protocol, it was decided that sufficient data had already been obtained. One participant in Part 1 also participated in Part 2. That participant is counted only in Part 1 for the participant flow.

Part 1: 7-day Dosing

Part 2: 28-day Dosing

Analysis population for the primary outcome, as defined in the registry: All participants who received ≥1 dose of investigational treatment were analyzed according to treatment received.

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: One participant in Part 1 also participated in Part 2. That participant is counted only in Part 1 for baseline characteristics.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Who Experienced at Least 1 Adverse Event (AE), measured over Up to approximately 139 days.

The primary posted endpoint is the percentage of participants who experienced at least one adverse event, assessed up to approximately 139 days. An adverse event is defined in the registry record as an untoward medical occurrence temporally associated with study intervention, whether or not it is considered related to that intervention. The definition includes unfavorable or unintended signs, abnormal laboratory findings, symptoms, and new or exacerbated disease.

This endpoint describes how many participants had one or more such events during the specified assessment period. It is a participant-level summary: someone with more than one event still contributes as a participant who experienced at least one event. It does not, by itself, describe the number, severity, duration, or cause of all events. The registry record reports percentages for the treatment groups, along with group sizes.

General statistical context: in an early-phase study, adverse-event summaries can describe the observed safety experience while treatment is being evaluated. A percentage is easier to interpret alongside its denominator because the same percentage can represent different amounts of information in groups of different sizes. This endpoint does not measure pulmonary vascular resistance or pulmonary blood volume. Although the study summary names changes in PVR and PBV among its objectives, their results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes the study as randomized, double-masked, and sequential, but does not report the statistical analysis plan, the randomization method, or the masking procedures. It lists 21 outcome measures and 18 posted secondary outcomes, while reporting 0 analyses. The available primary outcome is a percentage of participants with at least one adverse event, rather than a continuous measure or a time-to-event estimate.

What the percentage describes

For this endpoint, each participant is classified according to whether at least one adverse event was recorded during the assessment period. The posted values are 33.3%, 33.3%, 33.3%, and 80.0% in the listed groups. The accompanying group sizes are 6, 3, 9, and 5. The endpoint is therefore a proportion of participants, not a count of all adverse-event episodes and not a rate per unit of follow-up time. The registry definition includes events regardless of whether they were considered related to the intervention.

General statistical context: a proportion is a natural summary when the question concerns whether participants experienced an event. Its precision depends on the number of participants and the pattern of observed events. Reporting the denominator helps readers understand the scale of the data behind each percentage. An uncertainty interval can add information about precision, but confidence intervals for this endpoint are not reported in the registry record.

Why the groups should be read separately

The study is sequential and has distinct parts. Part 1 included an initial dosing period and a possible additional 7 days after review of pharmacokinetic and safety data. Part 2 used daily dosing from Days 1-28. The primary-outcome groups reported in the registry are the 360 μg and placebo groups from Part 1 and the 380 μg and placebo groups from Part 2. They are not presented as a single pooled comparison. The registry record does not give the decision rules or analysis methods for dose escalation, nor does it explain whether or how the results from different parts were intended to be combined.

General statistical context: comparisons are most straightforward when groups are part of the same planned comparison and assessed under compatible conditions. Differences in study part, dosing schedule, or follow-up can complicate direct interpretation. Randomization can support comparable groups within a randomized comparison, but the record does not describe the allocation process or provide a statistical comparison for these percentages. The design label alone does not establish that every listed group was compared in the same analysis.

What is and is not estimated

No p-value or confidence interval for the adverse-event percentage comparison is reported in the registry record. No adjusted effect estimate is reported. The result therefore supports a descriptive reading of the observed group percentages, not a claim about statistical significance or a quantified treatment effect. The registry record gives no adjusted model, covariate set, or test specification.

General statistical context: an unadjusted comparison uses the observed group summaries without accounting for other variables. An adjusted analysis may be appropriate when prespecified and supported by enough information, but the model and covariates would need to be reported to interpret it. No such method is reported. Likewise, a p-value would address compatibility with a specified statistical null model, not the clinical importance of a difference; no such test result is posted for this endpoint.

Planning illustrations and uncertainty

Planning illustrations use the observed effect as a reference and assume a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. These illustrations are planning calculations, not observed power and not the trial's own sample-size justification. The registry record does not report the study's sample-size rationale. Any planning result should be interpreted as conditional on those assumptions, not as evidence that the study was designed or sized according to them.

General statistical context: a planning calculation asks how many participants might be needed under assumed design conditions to detect a specified effect with a chosen operating characteristic. It does not show the probability that a completed study has discovered a true effect, and it cannot replace an uncertainty interval or a reported treatment comparison. With small observed groups, planning based on the observed effect can also be sensitive to the particular data used as its reference. The actual illustration values are not needed to interpret the posted adverse-event percentages.

Pharmacokinetic outcomes

The listed Part 1 secondary outcomes include plasma AUC from 0 to infinity and from 0 to 24 hours, maximum observed plasma concentration, concentration 24 hours after dosing, time to maximum concentration, apparent terminal half-life, and accumulation ratios. These measures characterize different aspects of drug concentration over time. Their numerical results and analysis methods are not reported in the registry record in the registry record described for this analysis. General statistical context: pharmacokinetic summaries can describe exposure and concentration patterns, but they are distinct from the participant-level adverse-event endpoint and from the stated PVR and PBV objectives.

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("Part 1: MK-5475 360 μg", "Part 1: Placebo", "Part 2: MK-5475 380 μg", "Part 2: Placebo")
n      <- c(6, 3, 9, 5)
events <- c(2, 1, 3, 4)
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  Part 1: MK-5475 360 μg  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Part 1: Placebo  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6
ARM  Part 2: MK-5475 380 μg  9  3  33.3  7.5  70.1  12.1  64.6  12.2  65.2
ARM  Part 2: Placebo  5  4  80.0  28.4  99.5  37.6  96.4  35.9  95.7

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 21 outcome measures and 18 posted secondary outcomes. It reports 0 analyses. The stated primary outcome is the percentage of participants with at least one adverse event. The study summary also identifies changes in pulmonary vascular resistance and pulmonary blood volume as objectives, and describes a primary hypothesis involving PVR reduction after 28 days. Results for PVR and PBV are not reported in the registry record.

The registry record does not report whether statistical testing was performed across multiple outcomes, whether any multiplicity adjustment was used, or which outcomes were designated for formal hypothesis testing. It also does not report a statistical analysis plan specifying a testing hierarchy or how secondary outcomes were to be interpreted. Without that information, the family of analyses intended for confirmatory interpretation cannot be established. The number of outcomes alone does not show whether multiplicity was controlled.

For the primary endpoint, the analysis population is described as all participants who received at least one dose of investigational treatment, analyzed according to treatment received. The record does not report a separate intention-to-treat population or describe exclusions from the endpoint analysis. It does not report how missing adverse-event information, incomplete follow-up, or participants with unavailable outcome data were handled. The primary outcome's timeframe is up to approximately 139 days, but details of individual follow-up duration are not reported in the registry record.

General statistical context: missing-data rules matter because conclusions can depend on whether participants with incomplete information are excluded, classified in a particular way, or addressed by a model. Multiplicity matters because examining several outcomes can increase the chance of at least one apparently unusual result under a collection of null hypotheses. Neither issue can be resolved from the outcome list alone. The posted percentages are best read as descriptive results for the stated groups and analysis population, without assuming unreported missing-data or multiplicity methods.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac failure (20.0%), covid-19 (11.1%), covid-19 pneumonia (11.1%), encephalopathy (11.1%), acute respiratory distress syndrome (11.1%).

For serious adverse events, the registry record reports the number at risk and the number affected in each group. In Part 1, 0 of 6 participants receiving MK-5475 360 µg and 0 of 3 receiving placebo were affected. In Part 2, 1 of 9 participants receiving MK-5475 380 μg and 1 of 5 receiving placebo were affected. The record lists 0 deaths in each group. These are participant counts, not percentages of all adverse-event episodes.

For other adverse events, the reported affected counts are 2 of 6 in Part 1 MK-5475 360 µg, 1 of 3 in Part 1 placebo, 2 of 9 in Part 2 MK-5475 380 μg, and 4 of 5 in Part 2 placebo. The registry record also lists serious-event terms with percentages: Cardiac failure, 20.0%; COVID-19, 11.1%; COVID-19 pneumonia, 11.1%; Encephalopathy, 11.1%; and Acute respiratory distress syndrome, 11.1%. The record does not provide group attribution for these listed terms in the registry record.

General statistical context: serious-event counts can be sparse, and a count of participants affected does not indicate how many events each participant had. The listed event terms should not be interpreted as rates or as evidence of a treatment relationship. The registry's definition of adverse event includes occurrences whether or not considered related to intervention; event attribution and comparative estimates are not reported in the registry record.

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

The posted primary results describe the proportion of treated participants who experienced at least one adverse event during follow-up up to approximately 139 days. They provide separate summaries for the Part 1 360 μg frespaciguat and placebo groups and the Part 2 380 μg frespaciguat and placebo groups. The percentages are 33.3%, 33.3%, 33.3%, and 80.0%, respectively, with group sizes of 6, 3, 9, and 5. Those figures are descriptive observations in small groups.

They do not establish whether the treatment groups differ statistically. No confidence intervals, p-values, or inferential comparisons for this endpoint are reported in the registry record. The different parts used different dosing structures and have separate placebo groups, so combining their results or treating the Part 1 and Part 2 comparisons as identical is not supported by the record. The registry's safety results also do not establish that any event was caused by the intervention.

The study summary states that the trial aimed to assess safety and tolerability and efficacy measured through changes in PVR and PBV, and it specifies a hypothesis about PVR reduction after 28 days. The posted primary endpoint is instead the adverse-event percentage. PVR and PBV results are not reported in the registry record, so the safety percentages do not answer the pulmonary vascular efficacy question. The registry entries described for this analysis also do not provide numerical results for the listed pharmacokinetic outcomes.

General statistical context: a study result is most informative when the endpoint, comparison, analysis population, uncertainty, and missing-data methods are all clear. Here, the endpoint and population description are available, but the registry record does not report comparative uncertainty or analysis methods for the percentage results. These limitations restrict interpretation to what was observed in the listed groups; they do not justify a broader conclusion about benefit, lack of benefit, or the effects of other doses.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the challenges in interpreting early-phase studies with sequential dose evaluation and small treatment groups. It is randomized and double-masked, but the registry record also describes a design in which Part 1 dosing could be extended after review of pharmacokinetic and safety data. Part 2 used a different dosing schedule. That structure makes it important to keep results tied to the part and regimen in which they were observed.

The primary posted outcome is a participant-level safety percentage, while the study summary emphasizes safety, tolerability, pharmacokinetics, pharmacodynamics, and changes in PVR and PBV. The mismatch between the stated efficacy objectives and the available primary result illustrates why readers should distinguish the study's objectives from the outcomes for which results are posted. The registry record does not report PVR or PBV results, nor does it report inferential analyses for the adverse-event percentages.

General statistical context: small groups can produce percentages that look quite different while remaining imprecise. Without uncertainty intervals or a stated comparative analysis, observed percentages should not be treated as proof of a group effect. Separating descriptive safety summaries from efficacy claims is also essential when several outcomes are listed and the analysis plan is unavailable.

The record identifies a treated-participant analysis population and reports serious and other adverse-event counts alongside the primary percentage. Those details support careful description of the available safety observations, but they do not substitute for information about missing data, multiplicity, event attribution, or the intended statistical model. The study therefore highlights the value of reporting methods alongside outcomes, especially when study parts and dose schedules differ.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary-outcome groups are small: the reported sizes are 6, 3, 9, and 5. The registry record does not report confidence intervals or p-values for the adverse-event percentages, so the precision of the group estimates and the uncertainty around comparisons cannot be assessed from the posted results. No inferential analysis is reported.

The study is sequential, and Part 1 includes a possible additional dosing period after pharmacokinetic and safety review. Part 2 has a different dosing schedule. The registry record does not describe the decision rules for proceeding with additional dosing, how dose selection was made, or how those design features were addressed analytically. The results listed for the primary outcome include only the Part 1 360 μg group and Part 2 380 μg group alongside their respective placebo groups; the reason other Part 2 dose groups are not included in these primary results is not reported in the registry record.

The outcome is the percentage of participants with at least one adverse event, which does not communicate event counts, severity, duration, or causal attribution. The registry record gives separate serious and other adverse-event counts, but the listed serious-event terms are not attributed to specific groups in the registry record described. PVR and PBV results, despite being named in the study objectives, are not reported in the registry record.

The analysis population is described as participants who received at least one dose, analyzed according to treatment received. Missing-data handling, follow-up completeness, multiplicity procedures, and a full statistical analysis plan are not reported in the registry record. The listed secondary outcomes concern Part 1 pharmacokinetics, but their numerical results are not included in the registry record described for this analysis. These gaps limit interpretation to the posted descriptive safety summaries.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Frespaciguat (MK-5475) in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD) (MK-5475-006) — NCT04370873.
• Registry record last updated 2025-05-28; status last verified 2025-05.
• Results first posted 2024-04-26.
• 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

NCT04370873 is a completed, randomized, double-masked Phase 1 study of inhaled frespaciguat, or MK-5475, and placebo in participants with pulmonary hypertension associated with COPD. The registry record reports enrollment of 22 and a sequential design with separate Part 1 and Part 2 dosing schedules.

The posted primary outcome is the percentage of participants experiencing at least one adverse event up to approximately 139 days. Results are 33.3% in Part 1 MK-5475 360 μg, 33.3% in Part 1 placebo, 33.3% in Part 2 MK-5475 380 μg, and 80.0% in Part 2 placebo. The group sizes are 6, 3, 9, and 5. The record reports serious-event and other-event counts and 0 deaths in each group.

The registry lists 21 outcome measures, 18 posted secondary outcomes, and 0 analyses. Comparative uncertainty estimates and PVR and PBV results are not reported in the registry record.