This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Low-Dose Tenecteplase in Covid-19 Diagnosed With Pulmonary Embolism (NCT04558125), a randomized phase 4 study. The primary outcome is Percent Improvement in Shock Index (Defined as Heart Rate Divided by Systolic Blood Pressure) 6 Hours After the TNK/Placebo Bolus..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04558125 |
| Phase | Phase 4 |
| Condition | Pulmonary Embolism, COVID |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 2 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Cedars-Sinai Medical Center |
| Results posted | Yes |
2. Clinical Question
Population
Hospitalized adults diagnosed with COVID-19 and acute intermediate-risk pulmonary embolism. The registry describes the intended population; it does not provide arm-specific participant characteristics.
Intervention
Low-dose intravenous bolus tenecteplase, identified as TNKase and described as 0.25 mg/kg, together with standard-of-care anticoagulation using heparin or enoxaparin.
Comparator
A placebo bolus together with standard-of-care anticoagulation using heparin or enoxaparin. The registry describes the placebo syringe as identical to the TNK syringe.
Primary question
What is the percent improvement in shock index, defined as heart rate divided by systolic blood pressure, 6 hours after the TNK or placebo bolus?
The clinical question concerns whether adding low-dose tenecteplase to anticoagulation is associated with a different early change in shock index than adding placebo to anticoagulation. The registry frames the study around patients with COVID-19 and acute intermediate-risk pulmonary embolism, in the context of concern about thromboembolic events and severe respiratory illness. Its stated primary endpoint is a physiologic measure rather than a direct measure of longer-term clinical status.
The planned comparison is between two treatment strategies, not between anticoagulation and no anticoagulation: standard-of-care anticoagulation is included in both arms. The record also lists clinical status at 24 hours after administration, assessed using a 7-point scale, as a secondary outcome. However, enrollment was 2, the study was terminated early, and it was never unblinded. Arm/group randomization information is unavailable, and no comparative primary-outcome results are reported in the registry record. The clinical question therefore remains unanswered by the posted results.
3. Trial Design
The registry classifies this as a Phase 4, randomized, parallel-group trial with quadruple masking. Its official title describes a randomized, double-blind, placebo-controlled trial. The brief summary calls it a prospective, multicenter, randomized two-arm study intended to enroll consecutive patients meeting eligibility criteria. The trial record identifies Cedars-Sinai Medical Center as the sponsor.
The intended intervention was a low-dose TNKase bolus with standard-of-care anticoagulation. The comparator was a placebo bolus with the same stated anticoagulation options, heparin or enoxaparin. These shared co-interventions matter when interpreting the intended contrast: the question was about adding TNK rather than substituting anticoagulation for another therapy. The registry describes the placebo syringe as identical to the TNK syringe. It does not report how masking was maintained in practice or whether masking remained intact.
The recorded start date is 2020-09-08, and the primary completion date is 2021-07-10. The status is terminated. Enrollment was 2. The primary-outcome description states that the study ended early and was never unblinded; it also says that arm/group randomization information is not available. Although randomization and masking are listed as design features, the record does not permit a reader to assess balance between groups or identify the treatment assignment of participants.
The primary endpoint was planned for assessment 6 hours after the TNK/placebo infusion. Clinical status at 24 hours after administration, based on a 7-point scale, is listed as a secondary outcome. The registry does not give a detailed statistical analysis plan or an explanation for termination in the registry record reported. Consequently, the design describes an intended comparative experiment, but the posted enrollment and outcome information do not support a treatment-effect comparison.
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: The study was terminated early and never unblinded. With only 2 subjects, statistical significance could never be demonstrated. Therefore, Arm/Group randomization information is not available.
Overall Study
| Stage | All Study Participants |
|---|---|
| STARTED | 2 |
| COMPLETED | 1 |
| NOT COMPLETED | 1 |
Reasons for not completing this period:
| Reason | All Study Participants |
|---|---|
| Death | 1 |
Analysis population for the primary outcome, as defined in the registry: The study was terminated early and never unblinded. With only 2 subjects, statistical significance could never be demonstrated. Therefore, Arm/Group randomization information is not available.
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 study was terminated early and never unblinded. With only 2 subjects, statistical significance could never be demonstrated. Therefore, Arm/Group randomization information is not available.
| Characteristic | Unit | All Study Participants |
|---|---|---|
| Participants analysed | 2 | |
| Age, Categorical: <=18 years | Participants | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 2 |
| Age, Categorical: >=65 years | Participants | 0 |
| Sex: Female, Male: Female | Participants | 1 |
| Sex: Female, Male: Male | Participants | 1 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 1 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 1 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 |
| Race (NIH/OMB): White | Participants | 2 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Region of Enrollment: United States | participants | 2 |
6. Primary Endpoint
The registry lists the primary outcome as Percent Improvement in Shock Index (Defined as Heart Rate Divided by Systolic Blood Pressure) 6 Hours After the TNK/Placebo Bolus., measured over 6 hours post TNK/placebo infusion.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is percent improvement in shock index 6 hours after the TNK or placebo bolus. Shock index is defined in the record as heart rate divided by systolic blood pressure. It combines information from two vital signs into a single measure, with the intention of capturing a change in circulatory status over the short period after treatment.
The registry illustrates the measure with a patient whose starting heart rate is 100 beats/min and systolic blood pressure is 100 mm Hg, giving a shock index of 1. After therapy, the example heart rate is 90 beats/min and systolic pressure is 110 mm Hg, giving a shock index of 0.81 and an improvement of 19%. The description also states that a normal shock index in healthy patients is between 0.5 and 0.7. These figures explain the endpoint; they are not participant results from this trial.
A change in a physiologic measure can be useful for assessing an early response, but it does not by itself establish what happened to symptoms, complications, survival, or longer-term health. The record gives no observed shock-index values, percent-improvement estimate, variability measure, or treatment-arm result. It states that the trial was terminated early and never unblinded, and arm/group information is unavailable. Thus, the endpoint is defined, but the posted record does not show the trial’s observed primary-outcome result.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The principal interpretive fact is that this trial enrolled 2 participants, was terminated early, and was never unblinded. The primary-outcome description explicitly says that statistical significance could never be demonstrated with only 2 subjects. More importantly for interpretation, the registry does not report an arm-specific primary-outcome estimate or even identify which randomized group participants belonged to. There is therefore no posted comparison of shock-index improvement between TNK and placebo.
The primary endpoint is defined as percent improvement in shock index 6 hours after the bolus. Its definition and the examples in the endpoint description explain what the measure means, but they are not study findings. No observed values, group summaries, confidence interval, p-value, or model-based estimate for the endpoint are reported in the registry record. Without those results, the direction and precision of any treatment contrast cannot be assessed. The registry reports 0 analyses.
The intended study design was randomized and masked, which would ordinarily support a controlled comparison if enrollment, outcome collection, and analysis were completed and reported. In this record, the planned design does not supply evidence of a comparative effect by itself. The absence of arm/group information also prevents a reader from checking how participants were allocated or whether outcome information could be attributed to either strategy. The stated early termination and lack of unblinding further limit what can be learned from the posted data.
The registry lists one secondary outcome: clinical status at 24 hours after TNK/placebo administration, based on a 7-point scale. It does not provide a comparative result for that outcome. The safety record lists serious adverse events and deaths for all study participants, but it does not assign those events to either treatment arm. These descriptive safety counts cannot establish whether the event pattern differed between strategies.
The record’s sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. Those assumptions describe an illustration, not the trial’s own design justification or observed power. No comparative effect estimate is reported in the registry record, and the illustration cannot fill that gap. A planning sample size is not evidence that the trial had a particular probability of detecting an effect.
Overall, the registry documents a planned randomized comparison and a defined early physiologic endpoint, but not an interpretable estimate of the primary treatment contrast. It does not establish that TNK improved shock index, that it failed to improve shock index, or that either strategy was safer. The correct reading is that the posted record is inconclusive for comparative efficacy and does not permit an arm-based safety comparison.
9. Statistical Methods Explained
The statistical interpretation begins with the distinction between a trial design and a trial result. Randomization, masking, and a parallel-group structure describe how a comparison was intended to be conducted. They do not provide an effect estimate. For a treatment comparison, readers need outcome information linked to the assigned groups, along with an analysis that estimates the contrast and its uncertainty. The registry lists randomization and quadruple masking, but the primary-outcome description says the study was never unblinded and that arm/group randomization information is not available.
What does the primary endpoint measure?
Shock index is defined as heart rate divided by systolic blood pressure. The endpoint concerns percent improvement in this index after the TNK or placebo bolus, assessed at 6 hours. An endpoint expressed as improvement requires a reference measurement and a later measurement. In general, a change score describes how an individual’s measure differs over time, while a treatment comparison asks whether that change differs between treatment strategies. A within-group change alone cannot distinguish a treatment effect from changes that might occur over time in either group.
The registry includes an illustrative example and a healthy-range description for shock index. Those numbers clarify the scale but are not observations from the enrolled participants. No participant-level values or group-level endpoint summaries are reported. The endpoint field also gives no unit, parameter, or dispersion value. Without those results, neither the observed change nor the variability around a treatment contrast can be assessed.
What would an effect estimate and confidence interval tell readers?
In general, an effect estimate describes the size and direction of a comparison, while a confidence interval describes the range of values reasonably compatible with the data under the model and assumptions used. A narrow interval indicates more precision than a wide interval; an interval that spans effects in different directions may leave the practical interpretation uncertain. A p-value addresses compatibility with a specified null hypothesis under statistical assumptions, not the probability that a treatment works or that the null hypothesis is true.
No primary-outcome estimate, confidence interval, or p-value is reported in the registry record. The record’s statement that statistical significance could never be demonstrated with only 2 subjects should not be converted into a claim about the size or direction of an effect. Statistical significance and clinical importance are different questions, and neither can be evaluated from an unreported comparative estimate. The absence of an estimate also means that precision cannot be judged.
Why does the analysis need to match the outcome and design?
As a general principle, statistical methods should reflect the outcome’s scale, the way observations were collected, and the planned comparison. A continuous measurement, a categorical status scale, and an event count do not necessarily call for the same model. A repeated measure also raises a different question from a single measurement: an analysis may need to account for the relationship between measurements from the same participant. These are general considerations, not descriptions of methods used in this trial. The registry record does not report the statistical model, covariate adjustment, handling of baseline measurements, or method for calculating uncertainty.
Over-dispersion is a general concern in analyses of count outcomes when the observed variability is greater than a model assumes. If it is ignored, standard errors may be too small and resulting intervals or tests may be misleading. It is not a stated feature of the primary shock-index endpoint, and the record does not say that an over-dispersion adjustment was used. The example serves to distinguish a general statistical issue from a documented trial method.
How should the planning illustration be read?
The record describes planning assumptions for an illustration computed from an observed effect: a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It describes the effect to detect as a stated fraction of the observed effect. These are planning assumptions, not evidence of the trial’s prespecified sample-size justification or statistical analysis plan. The record does not report such a justification or plan.
Any sample-size figures associated with a planning illustration should be read as hypothetical participants per arm under its assumptions. They are not observed enrollment, evidence of adequate enrollment, or observed power. The trial’s recorded enrollment is 2, and the posted record does not give an observed comparative effect from which readers could assess the illustration’s relevance. Planning calculations cannot recover treatment assignments, outcome results, or uncertainty that the registry does not report.
For this record, the central statistical limitation is not the choice between competing analysis methods; it is that the comparative outcome information needed to use such methods is absent. The registry reports 0 analyses, no arm-specific primary endpoint result, and no treatment allocation information. Statistical concepts can clarify what evidence would ordinarily be interpreted, but they cannot substitute for the missing comparison.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists the primary endpoint as percent improvement in shock index 6 hours after the bolus. It also lists clinical status at 24 hours after TNK/placebo administration, assessed using a 7-point scale, as a secondary outcome. The record reports 2 outcome measures and 0 analyses. It does not provide results for either outcome in a form that permits a treatment-group comparison.
When a study evaluates multiple outcomes or performs multiple statistical tests, the chance of at least one apparently positive finding can increase. Statistical plans may address this multiplicity by identifying a primary outcome, specifying how secondary outcomes will be interpreted, or adjusting inference. That is a general explanation; the registry record does not report a multiplicity strategy, a hierarchy of tests beyond identifying the primary and secondary outcomes, or any adjustment for multiple comparisons. Because no comparative results are reported, there is no basis for assessing how multiplicity affected the findings.
The registry does not report the number of participants with missing primary or secondary outcome measurements, the reasons for missingness, or any imputation or other missing-data method. It also does not describe an analysis population, such as whether participants were to be analyzed according to randomized assignment or according to treatment received. These details are not reported in the registry record and should not be inferred from the randomized design label.
The primary-outcome description says the study was terminated early and never unblinded. That information explains why the record does not support a completed comparative analysis, but it does not establish how any missing outcome data would have been handled. No prespecified analysis population, missing-data procedure, or multiplicity plan is reported. The absence of these details limits reproducibility and makes it impossible to judge how the intended analysis would have treated incomplete observations.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| All Study Participants | 1 | 2 | 50.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| All Study Participants | 1 of 2 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| All Study Participants | 1 of 2 |
Most frequent serious adverse event terms
| Event term | Organ system | All Study Participants |
|---|---|---|
| Respiratory Failure | Respiratory, thoracic and mediastinal disorders | 1 of 2 |
| Gastrointestinal Bleeding | Gastrointestinal disorders | 1 of 2 |
Most frequent non-serious adverse event terms
| Event term | Organ system | All Study Participants |
|---|---|---|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | 1 of 2 |
| Productive cough | Respiratory, thoracic and mediastinal disorders | 1 of 2 |
| Hypotension | Cardiac disorders | 1 of 2 |
Serious events with the highest arm-level rate: respiratory failure (50.0%), gastrointestinal bleeding (50.0%).
The registry’s adverse-event summary is for “All Study Participants,” not separate treatment arms. It records 2 participants at risk for serious adverse events and 1 affected, and 2 at risk for other adverse events and 1 affected. It also records 1 death. Because the study was never unblinded and arm/group randomization information is unavailable, these figures cannot be attributed to TNK or placebo, nor can they support a comparison between the strategies.
The record names Respiratory Failure and Gastrointestinal Bleeding among the top serious-event terms, each reported as 50.0%. These percentages describe the registry’s serious-event summary; they are not evidence of a treatment-specific risk. The record does not report arm-level denominators or outcomes, and it does not provide enough detail to infer whether event categories overlap or how events were related to treatment.
Serious adverse events, other adverse events, and deaths are distinct summaries and should not be treated as interchangeable measures. The small recorded enrollment and absence of unblinded group information make these counts descriptive only. They do not establish comparative safety, causation, or the frequency of these events in a broader population. The registry record does not report an arm-based safety analysis.
12. What the Result Does, and Does Not, Mean
The record establishes that investigators planned a randomized, quadruple-masked, parallel-group comparison of low-dose tenecteplase plus anticoagulation against placebo plus anticoagulation in hospitalized adults with COVID-19 and acute intermediate-risk pulmonary embolism. It defines a primary endpoint based on percent improvement in shock index at 6 hours and lists clinical status at 24 hours as a secondary outcome. It also records early termination and enrollment of 2 participants.
Those details do not establish the effect of tenecteplase on shock index or clinical status. No arm-specific primary result, comparative estimate, confidence interval, or p-value is reported. The registry states that the study was never unblinded and that arm/group randomization information is unavailable. The posted record therefore cannot show whether the groups differed, how large any difference might have been, or how precisely such a difference was estimated.
The safety counts also do not establish a comparative safety profile. They are pooled across all study participants, without treatment-arm attribution. The named serious-event terms and recorded death should be read as descriptive reports from this trial record, not as evidence that one treatment strategy caused or prevented an event.
Likewise, an absence of a statistically significant result is not demonstrated by this record: no comparative test result is reported. The registry’s statement that statistical significance could never be demonstrated with only 2 subjects is an explicit limitation of this terminated study, not a result showing no effect. The record cannot distinguish a meaningful effect from no effect or from an effect in the opposite direction.
The appropriate conclusion is narrow: the trial record documents a clinically motivated question and an intended controlled design, but it does not provide a usable efficacy comparison or arm-based safety comparison. The study’s stated question remains unresolved by the posted results. Its findings should not be extended beyond the information recorded or interpreted as evidence for or against either treatment strategy.
13. Why This Trial Matters Statistically
This trial is statistically important because it illustrates the difference between a carefully described research question and an answer supported by comparative data. The registry identifies a randomized, quadruple-masked, parallel design and a specific physiologic endpoint. Those features clarify what the investigators intended to compare. But enrollment was 2, the study was terminated, and the record says it was never unblinded. The treatment assignments and comparative endpoint results are unavailable.
Randomization is useful because it aims to make treatment groups comparable in expectation, reducing the risk that measured or unmeasured baseline differences explain an observed contrast. In a completed, reported trial, the analysis can estimate the difference between assigned strategies and describe uncertainty. Here, the randomization label cannot substitute for group-linked outcomes. Since arm/group information is unavailable, the benefits of a randomized comparison cannot be evaluated from the posted record.
The case also demonstrates why a defined endpoint is not the same as an observed result. Shock index is defined and its timing is specified, but no study-specific endpoint values are reported. Without those values, readers cannot determine the effect’s direction, magnitude, or precision. Likewise, pooled adverse-event counts cannot establish which strategy had which safety experience.
Finally, planning assumptions and inferential results serve different purposes. The record describes assumptions for a sample-size planning illustration, but such an illustration is not observed power and does not provide a treatment estimate. Statistical methods can quantify evidence only when relevant outcome data and analysis details are available. The central lesson is that a trial’s design, endpoint definition, and planning framework do not resolve its clinical question when the comparative results are not reported.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The main trial-specific limitation is the small recorded enrollment: 2 participants. The registry states that the study was terminated early and never unblinded. It also states that arm/group randomization information is not available. Together, these registry entries prevent readers from reconstructing a treatment comparison or assigning reported outcomes to either strategy.
The primary endpoint is described, but observed shock-index values and percent improvement are not reported. The record gives no group summaries, measure of variability, effect estimate, confidence interval, or p-value. It also reports 0 analyses. Consequently, the endpoint’s observed direction and precision cannot be assessed. The stated endpoint timeframe is 6 hours after the bolus, while the listed secondary clinical-status outcome is at 24 hours; no comparative result is reported for either.
The pooled adverse-event figures do not identify treatment arm, and the registry does not provide arm-level safety results. The recorded death and serious-event terms therefore cannot be used to compare strategies or attribute causation. The record does not report the reasons for termination, the detailed participant flow, baseline characteristics by group, missing-outcome handling, analysis population, or statistical analysis plan. Those items are not reported in the registry record and should not be reconstructed by assumption.
The intended population is described as hospitalized adults with COVID-19 and acute intermediate-risk pulmonary embolism, but the registry entries do not give participant characteristics that would show how closely the enrolled participants matched that description. The results cannot be generalized from this record because a comparative result is not available. These limitations do not demonstrate that the treatment had no effect; they mean that the record does not provide enough information to estimate or interpret a treatment effect.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Low-Dose Tenecteplase in Covid-19 Diagnosed With Pulmonary Embolism — NCT04558125.
- Registry record last updated 2021-10-26; status last verified 2021-10.
- Results first posted 2021-10-26.
- 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.
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18. Record Summary
NCT04558125 is a Phase 4 randomized, quadruple-masked, parallel-group trial sponsored by Cedars-Sinai Medical Center. It planned to compare low-dose TNKase plus standard-of-care anticoagulation with placebo plus standard-of-care anticoagulation in hospitalized adults with COVID-19 and acute intermediate-risk pulmonary embolism. The primary endpoint was percent improvement in shock index 6 hours after the bolus. Clinical status at 24 hours, based on a 7-point scale, was listed as a secondary outcome.
The recorded study start date is 2020-09-08, primary completion date is 2021-07-10, and status is terminated. Enrollment was 2. The record says the trial was never unblinded and that arm/group randomization information is unavailable. It reports 0 analyses and no comparative primary-outcome result. Adverse-event counts are pooled across all study participants and cannot be assigned to treatment arms. The registry record therefore describes the intended design and outcomes but does not provide an interpretable efficacy or comparative safety estimate.