Massive Pulmonary Embolism: Trial of Non-immunogenic Recombinant Staphylokinase VS Alteplase FORPE: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Massive Pulmonary Embolism: Trial of Non-immunogenic Recombinant Staphylokinase VS Alteplase FORPE (NCT04688320), a randomized phase 3 study. The primary outcome is Death From All Causes.

2. Clinical Question

The trial was registered for patients with massive pulmonary embolism and compared two thrombolytic regimens. Its stated objective was to evaluate efficacy and safety. The primary outcome is a count of participants who died from any cause within the specified timeframe, rather than a measure limited to deaths attributed to pulmonary embolism.

The randomized comparison can describe the observed difference between the groups in this trial. Interpretation also depends on the endpoint definition, analysis population, precision of the estimate, and the analysis reported by the sponsor. The registry record identifies the sponsor's analysis as a non-inferiority analysis, but the non-inferiority margin and the other original design assumptions are not reported in the registry record.

3. Trial Design

FORPE is a phase 3, randomized, multicenter, open-label comparative trial with a parallel-group design. The registry record reports enrollment of 310 participants and a completed status. The trial start date was 2020-12-15, and the primary completion date was 2023-07-27. The sponsor was Supergene, LLC.

Participants were allocated to recombinant nonimmunogenic staphylokinase or alteplase. The staphylokinase regimen was a single intravenous bolus of 15 mg (2,235,000 IU) administered over 10-15 seconds, regardless of body weight. The alteplase regimen was a 10 mg bolus followed by 90 mg as an intravenous infusion over 2 hours, with a maximum dose of 100 mg; for patients weighing less than 65 kg, the total dose should not exceed 1.5 mg / kg. These are the regimens described in the registry record.

The trial was open label, with no masking reported. The registry record does not report how the randomization sequence was generated, whether allocation was concealed, or whether endpoint assessment used any blinded procedures. Such details matter when considering the possibility of bias, particularly for outcomes that require judgment. Death is a comparatively direct endpoint, although the registry does not provide further details about outcome ascertainment.

The primary endpoint was death from all causes within 7 days, assessed in the per-protocol population. The posted primary analysis includes 145 participants in the recombinant nonimmunogenic staphylokinase group and 146 in the alteplase group. Those analysis counts are not the same description as the overall enrollment figure; the registry record does not explain the difference or provide a detailed flow of participants from enrollment to the primary analysis.

The registry also lists secondary efficacy and safety outcomes, including pulmonary artery pressure measures, haemodynamic collapse, recurrent pulmonary embolism, deaths, and bleeding outcomes. The trial's original sample-size justification, detailed statistical analysis plan, and procedures for handling departures from protocol 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: in the per-protocol population

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: 310 patients were randomly assigned to receive either non-immunogenic staphylokinase (n=155) or alteplase (n=155)

6. Primary Endpoint

The registry lists the primary outcome as Death From All Causes, measured over within 7 days.

The primary endpoint counts participants who died from any cause within 7 days. It is defined for the per-protocol population. Because it includes deaths from all causes, it does not require the registry's outcome definition to attribute a death specifically to pulmonary embolism. This differs from the listed secondary endpoint of death from pulmonary embolism, which has a different cause-specific definition and a different timeframe.

In general, all-cause death is used as an endpoint because it is a clinically important event and its definition does not depend on deciding which disease or treatment caused a death. That can reduce ambiguity in classification compared with cause-specific outcomes. This general consideration does not establish why the trial's designers selected this endpoint; the rationale is not reported in the registry record.

The endpoint is a binary event for each participant: a participant either had a recorded death within the specified timeframe or did not. The posted results give event counts and the numbers analyzed in each arm. A comparison of those counts is informative about the observed outcomes in the trial, but it does not by itself resolve how precisely the underlying group difference is estimated. The confidence interval and the analysis reported by the sponsor also need to be considered.

Using the per-protocol population means the primary result concerns participants included in that analysis population, rather than necessarily every randomized participant. The registry record does not report the criteria used to define the per-protocol population or how missing endpoint data were handled.

7. Results Posted in the Registry

• Alteplase: 2.7% (4/146) versus 2.1% (3/145) on control; risk difference 0.7 percentage points (95% CI -2.8 to 4.2), risk ratio 1.32 (0.30–5.81); unadjusted two-proportion z-test p = 0.709.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Death From PE

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Alteplase: 1.4% (2/146) versus 2.8% (4/145) on control; risk difference -1.4 percentage points (95% CI -4.7 to 1.9), risk ratio 0.50 (0.09–2.67); unadjusted two-proportion z-test p = 0.405.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Alteplase and the control. The interval gives the range of effects that remain compatible with the data.

Death From All Causes

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Alteplase: 2.7% (4/146) versus 4.1% (6/145) on control; risk difference -1.4 percentage points (95% CI -5.6 to 2.8), risk ratio 0.66 (0.19–2.30); unadjusted two-proportion z-test p = 0.513.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Alteplase and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes that extend beyond the primary all-cause death endpoint. These include pulmonary artery pressure measures at specified visits, haemodynamic collapse, recurrent pulmonary embolism, death from pulmonary embolism, all-cause death at a later timeframe, a combined outcome involving collapse, recurrent embolism and death, and bleeding-related safety outcomes. Together, they address haemodynamic status, recurrent events, mortality, and safety rather than a single outcome dimension.

The posted secondary comparisons for death from pulmonary embolism and all-cause death use a 30-day timeframe, unlike the primary endpoint's 7-day timeframe. Other listed outcomes also have their own definitions and assessment times. They can provide context about the broader clinical course, but they should not be substituted for the primary endpoint or treated as if they were repeated measures of the same event.

Across the secondary outcomes, the registry record does not provide a complete set of detailed estimates for every listed measure in the information available for this account. Results for the other listed endpoints are not reported in the registry record. The pattern therefore cannot be summarized as though all outcomes showed a consistent effect in one direction. The available secondary results should be read as separate comparisons, with their own uncertainty and definitions.

In general, multiple secondary comparisons raise the possibility of chance findings: the more outcomes examined, the greater the opportunity for an apparently notable result to occur even if there is no underlying effect. Unadjusted secondary results carry less weight when no multiplicity plan is reported, because their p-values do not account for the number of comparisons. The registry record does not report whether the secondary analyses were adjusted, prioritized, or prespecified in a detailed analysis plan. Their role is therefore supportive and exploratory in interpretation, rather than a replacement for the primary result.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Systolic Pulmonary Artery Pressure Measures (V1, V2, V4, V5)
• Haemodynamic Collapse
• Recurrent Pulmonary Embolism (PE)
• Death From PE
• Death From All Causes
• Haemodynamic Collapse Within 7 Days + Recurrent PE Within 7 Days + Death From All Causes Within 30 Days
• Safety Endpoint - Haemorrhagic Stroke
• Safety Endpoint - BARC Type 3+5 Bleeding

9. Statistical Interpretation

10. Statistical Methods Explained

For a binary endpoint, each participant is classified as having or not having the event within the defined timeframe. The primary result is therefore a comparison of event counts between the two treatment groups. The posted counts are 3 among 145 participants in the staphylokinase group and 4 among 146 in the alteplase group. The endpoint is all-cause death within 7 days in the per-protocol population.

What does the risk difference represent?

A risk difference compares the event proportions in the groups by subtraction. Its sign depends on the order in which the groups are compared. The re-calculated estimate is 0.007 for alteplase relative to staphylokinase. A positive value in this comparison means the observed event proportion was higher in the alteplase group; it does not, by itself, demonstrate a reliable difference. The confidence interval, from -0.029 to 0.042, includes zero and extends in both directions.

The risk-difference estimate is an unadjusted re-calculation from the posted summary counts, rather than the sponsor's reported analysis. It does not account for covariates or other features that might have been included in an analysis of participant-level data. The registry record does not report enough information to reproduce the sponsor's analysis or determine precisely why its result differs.

How should the p-value be read?

The unadjusted p-value of 0.709 describes how compatible the observed data are with a null model of no difference, under the assumptions of that calculation. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. A large p-value does not establish equivalence or non-inferiority. Those conclusions require an appropriate prespecified framework, including a non-inferiority margin and a suitable confidence-interval interpretation.

The sponsor's analysis is reported as Welch's t-test, with an odds ratio of 0.75, a 95% confidence interval from 0.11 to 4.52, and p < 0.05, and is categorized as non-inferiority. The reported method and effect measure are presented as recorded. Since the registry flags a discrepancy between the sponsor result and the simple re-calculation, the sponsor's own analysis takes precedence for describing the posted sponsor analysis. The margin, detailed model specification, and explanation of the discrepancy are not reported in the registry record.

What does a confidence interval add?

A confidence interval expresses the range of effect estimates compatible with the data and the method used, under the method's assumptions. It communicates precision as well as direction. If an interval includes the null value for the effect measure, the data do not distinguish that null value from the estimates inside the interval at the corresponding confidence level. General interpretation should consider the full interval, not just whether a p-value crosses a threshold.

For a risk difference, zero is the null value: no difference between the compared event proportions. The re-calculated interval includes zero. The sponsor reports an odds-ratio interval, for which the null value is one; its interval is also broad. These are different effect measures and analyses, so their estimates and intervals should not be treated as interchangeable.

Why is the analysis population important?

The registry defines the primary endpoint in the per-protocol population. This population can differ from all randomized participants, depending on the protocol rules and exclusions. The registry record does not state the criteria for inclusion in the per-protocol analysis, the number excluded from it, or the reasons for exclusion. It also does not report the missing-data approach. Those details are important for understanding how the analysis population was formed and whether the result could be affected by post-randomization exclusions.

In general, randomized comparisons are interpreted in light of the population analyzed. An intention-to-treat analysis, which retains participants in their assigned groups, and a per-protocol analysis answer related but not identical questions. The registry record identifies the primary population as per protocol; it does not report an intention-to-treat primary result or allow a comparison of analysis populations.

What does the trial's non-inferiority label establish?

The registry categorizes the sponsor's reported analysis as non-inferiority. A non-inferiority analysis asks whether the effect is sufficiently close to a comparator according to a prespecified margin, rather than simply testing whether there is any difference. The margin and the statistical plan are not reported in the registry record. The label alone therefore does not permit an independent assessment of the non-inferiority conclusion. In general, the margin, analysis population, confidence interval, and adherence to the planned analysis all affect that assessment.

The registry record reports one analysis for the primary endpoint and lists multiple secondary outcomes. It does not report whether interim analyses were planned or conducted, how secondary comparisons were handled, or whether adjustments for multiple testing were prespecified. These omissions limit interpretation of the total set of reported findings, even when a particular endpoint has a clear count and comparison.

11. Confidence Intervals and Precision

The unadjusted re-calculation for the primary endpoint estimates a risk difference of 0.007 for alteplase relative to recombinant nonimmunogenic staphylokinase. Its confidence interval runs from -0.029 to 0.042. Because the interval includes zero and extends to values on either side, the posted event counts do not estimate the direction of the difference with precision. The interval also allows for effects of differing sizes, so the point estimate alone should not be treated as a settled description of the underlying contrast.

In general, a confidence interval is a way to express uncertainty around an estimate, based on the data and method used. A narrower interval indicates greater precision under those assumptions; a wider interval indicates less precision. It is not a guarantee that the true effect lies inside the interval, nor does it account for biases or limitations that the analysis method does not address.

The sponsor's reported odds ratio is 0.75 with a 95% confidence interval from 0.11 to 4.52. That interval is broad and includes the odds-ratio null value of one. It is a distinct reported analysis from the unadjusted risk-difference re-calculation. The registry record flags a discrepancy, so the sponsor's own analysis takes precedence in describing its reported result; the registry does not provide enough detail to resolve the difference or assess the non-inferiority margin.

The primary analysis is based on 145 participants in one group and 146 in the other, with 3 and 4 events, respectively. With relatively few recorded events, the estimate can be sensitive to small changes in event counts. This general feature of sparse binary outcomes reinforces the importance of reading the full interval rather than relying only on the point estimate or p-value.

12. 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 sample-size figures are planning illustrations based on the observed effect, not the trial's original design calculation. The registry record's stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The trial's own sample-size justification and original design assumptions are not reported in the registry record.

For the binary outcomes discussed, the figures are participants per arm, not a combined total. The 80% power column means the illustrated number of participants per arm that would give an 80% chance of detecting the specified effect under the stated assumptions, if that effect and model were correct. The 90% power column has the same interpretation at a higher target chance of detection. Neither column describes the trial's observed statistical power.

The rows represent planning for 100%, 75%, and 50% of the observed effect. Smaller effects require more participants to detect with the same target power, because they are harder to distinguish from random variation. For the primary endpoint, the figures range from 8,186 participants per arm for 80% power and 10,959 for 90% power when planning for 100% of the observed effect, to 30,516 and 40,852 when planning for 50% of the observed effect. Planning for 75% of the observed effect gives 14,059 participants per arm for 80% power and 18,820 for 90% power.

These figures are not observed power, and they do not show what the trial was originally designed to detect. They are conditional illustrations derived from the observed effect and the stated planning assumptions. Because observed effects from small event counts can be uncertain, such illustrations should not be read as a definitive sample-size recommendation.

13. 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 = 0.021; treatment proportion p₁ = 0.027; average p̄ = 0.024.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2166 = 0.4246.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2166 = 0.1823.
4. n = (0.4246 + 0.1823)² / (0.0067)² = 8,185.9, rounded up to 8,186 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 <- 0.0206896551724138                          # control proportion
p1 <- 0.0273972602739726                          # 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(4688320)
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 = 8,186 (80% power), 10,959 (90% power)
 75% of observed effect: n per arm = 14,059 (80% power), 18,820 (90% power)
 50% of observed effect: n per arm = 30,516 (80% power), 40,852 (90% power)
power.prop.test: 8185.9 
Simulated power at n = 8,186 per arm: 0.805 (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.

14. Analyses Reported by the Sponsor

The registry reports the sponsor's primary analysis as a non-inferiority analysis using Welch's t-test, with an odds ratio of 0.75, a 95% confidence interval from 0.11 to 4.52, and p < 0.05. The registry also flags a discrepancy between that reported analysis and the unadjusted re-calculation from the posted event counts. The sponsor's own analysis takes precedence when describing the sponsor's reported result.

The re-calculation uses the posted counts and gives a risk difference of 0.007, a confidence interval from -0.029 to 0.042, and an unadjusted p-value of 0.709. It is a simple, unadjusted comparison and is not a substitute for an analysis based on the trial's participant-level data or the sponsor's statistical procedures. The reported odds ratio and re-calculated risk difference are different measures, so their numerical estimates should not be compared as if they represented the same scale.

The registry record does not report the non-inferiority margin, full model details, or an explanation for the discrepancy. Without those details, the sponsor's non-inferiority result cannot be independently verified or interpreted against its intended threshold. The reported label should therefore be distinguished from what can be concluded from the posted summary counts alone.

15. Multiplicity, Missing Data and Analysis Populations

The registry record identifies one primary endpoint and lists multiple secondary outcomes. It does not report a detailed multiplicity strategy, including whether a hierarchy of outcomes was prespecified, whether alpha was allocated across comparisons, or whether p-values were adjusted. Without those details, nominal statistical findings across multiple outcomes should be interpreted cautiously. In general, multiplicity matters because repeated testing can increase the chance of at least one apparently positive result by chance.

The record also does not report whether interim analyses were planned or conducted, whether any stopping boundaries were used, or whether the analysis plan changed during the trial. These items should not be inferred from the completed status or the posted results. The trial's full statistical analysis plan is not reported in the registry record.

The primary endpoint is specified for the per-protocol population. The criteria defining that population, the number and reasons for any exclusions, and the treatment of missing outcome data are not reported in the registry record. The primary arm counts are 145 and 146, while overall enrollment is reported as 310; the record does not provide a participant flow explaining the relationship between those figures. It also does not report an intention-to-treat analysis of the primary outcome.

These omissions limit assessment of how robust the primary and secondary results are to choices about analysis populations or missing observations. In general, missing-data methods and post-randomization exclusions can affect a comparison if they differ between groups or relate to the outcome. The registry does not provide the information needed to determine whether that occurred in this trial. This is a limit on what can be evaluated from the registry record, not evidence that any particular bias occurred.

16. 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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death from all causes (4.1%), haemodynamic collapse (2.1%), haemorrhagic stroke (2.1%), recurrent pe (1.4%), cerebral oedema (1.4%).

The adverse-event results report serious events among 9 participants at risk of 145 in the recombinant nonimmunogenic staphylokinase group and 17 participants at risk of 146 in the alteplase group. Other adverse events are reported for 72 participants at risk of 155 in the staphylokinase group and 86 at risk of 155 in the alteplase group. The registry also lists 6 deaths for the staphylokinase group and 4 for the alteplase group in this adverse-event summary.

The registry lists serious-event terms and percentages, including death from all causes at 4.1%, haemodynamic collapse at 2.1%, haemorrhagic stroke at 2.1%, recurrent PE at 1.4%, cerebral oedema at 1.4%, and ischaemic stroke at 0.7%. The record does not specify a treatment-group breakdown for these term percentages in the information, so they should not be assigned to an individual arm.

These safety counts are distinct from the primary endpoint counts, which concern all-cause death within 7 days in the per-protocol population. The registry does not provide enough information to reconcile the different death counts, populations, or reporting windows. Serious-event and other-event summaries should be interpreted in light of their denominators and definitions, which are not fully described in the record.

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

The posted primary outcome shows 3 deaths within 7 days among 145 participants in the recombinant nonimmunogenic staphylokinase group and 4 among 146 in the alteplase group, for the per-protocol analysis. The unadjusted re-calculation estimates a risk difference of 0.007 for alteplase relative to staphylokinase, with a confidence interval from -0.029 to 0.042. This interval crosses zero, so the summary counts do not establish a clear direction of difference.

The result does not prove that the treatments have identical effects. A non-significant unadjusted comparison is not an equivalence test, and the posted counts alone cannot demonstrate non-inferiority. The sponsor reports a non-inferiority analysis, but the margin and sufficient model details are not reported in the registry record. The registry flags a discrepancy; the sponsor's own analysis takes precedence when describing its reported result, while the discrepancy limits independent verification.

The primary outcome addresses death from any cause within 7 days in the per-protocol population. It does not, by itself, describe later deaths, recurrent embolism, haemodynamic outcomes, or all aspects of safety. Those are separate outcomes with distinct definitions and timeframes. Nor does the result establish that either regimen is appropriate for an individual patient; the trial comparison is not personal medical advice.

Interpretation is also constrained by information not reported in the registry record, including the original sample-size rationale, detailed statistical plan, missing-data methods, and criteria for the per-protocol population. The trial's randomized design supports a comparative interpretation, but the posted summary does not resolve every question about conduct or analysis. The most defensible reading is to focus on the observed counts, the broad uncertainty, and the limits of the reported analysis rather than treating the point estimate or non-inferiority label as definitive on its own.

18. Why This Trial Matters Statistically

This trial illustrates why a treatment comparison cannot be reduced to which group has fewer observed events. The primary event counts are close, but the estimate is uncertain: the unadjusted risk-difference confidence interval extends across zero and in both directions. Precision matters because a point estimate from a small number of events can be an unstable guide to the size or direction of the underlying effect.

It also illustrates the distinction between a superiority-style test of difference and a non-inferiority question. A non-inferiority conclusion relies on a prespecified margin and a suitable analysis. The registry labels the sponsor analysis as non-inferiority, but the margin is not reported. That missing design detail prevents independent evaluation of the claim, even though the sponsor's result should take precedence over a simple re-calculation when describing the sponsor's own analysis.

The record also provides an example of why population definitions and analysis transparency matter. The primary result is per protocol, while the overall enrollment figure is 310. A detailed participant flow, analysis-population criteria, and missing-data methods are not reported. Those details would help readers understand who contributed to the primary estimate and how it relates to the randomized population.

Finally, the trial lists a range of secondary efficacy and safety outcomes. These can broaden the clinical picture, but multiple outcomes require cautious interpretation, particularly when adjustment and prioritization plans are not reported. The statistical lesson is to distinguish the primary comparison from secondary signals, and to keep uncertainty and reporting limitations visible when interpreting both.

19. 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 registry record leaves several trial-specific questions unresolved. Although the trial is described as randomized, the method used to generate the sequence and the approach to allocation concealment are not reported. The trial was open label with no masking, and the record does not describe whether any endpoint assessment was blinded. These details affect how readers assess the potential for bias, though the record does not establish that bias occurred.

The primary endpoint is analyzed in the per-protocol population, but the criteria for that population and the reasons for any exclusions are not reported. The record reports overall enrollment of 310 and primary analysis counts of 145 and 146, without a participant-flow account connecting them. Missing outcome data and the methods used to handle them are also not reported. The trial's original sample-size justification and full statistical analysis plan are not reported.

The sponsor's reported non-inferiority analysis differs from the simple re-calculation based on posted summary counts. The registry flags this discrepancy, and the sponsor's own analysis takes precedence in describing its reported result. However, the non-inferiority margin, detailed model specification, and explanation of the difference are not reported, which limits independent assessment.

Only a subset of secondary outcomes has detailed numerical results in the record used for this account; results for the other listed endpoints are not reported in the registry record. The multiplicity plan and interim-analysis procedures are also not reported. Safety summaries include different at-risk counts and death totals from the primary analysis, but the record does not give enough detail to reconcile those figures. These are limitations in the information available for interpretation, not evidence that a particular result is biased or incorrect.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Massive Pulmonary Embolism: Trial of Non-immunogenic Recombinant Staphylokinase VS Alteplase FORPE — NCT04688320.
• Registry record last updated 2025-04-02; status last verified 2025-03.
• Results first posted 2025-04-02.
• 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.

23. Record Summary

FORPE is a completed, randomized, multicenter, open-label, parallel phase 3 trial comparing recombinant nonimmunogenic staphylokinase with alteplase in patients with massive pulmonary embolism. Enrollment was 310. The trial start date was 2020-12-15, and the primary completion date was 2023-07-27. The sponsor was Supergene, LLC.

The primary endpoint was all-cause death within 7 days in the per-protocol population. The posted analysis included 145 participants in the staphylokinase group and 146 in the alteplase group, with 3 and 4 events, respectively. The registry reports a sponsor non-inferiority analysis and flags a discrepancy with an unadjusted re-calculation from the summary counts; the sponsor's own analysis takes precedence in describing its reported result.

The registry lists secondary outcomes covering haemodynamic measures, recurrent events, mortality, and safety. Detailed information about the original design assumptions, analysis plan, multiplicity, missing data, and per-protocol criteria is not reported in the registry record.