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 A Study to Evaluate the Safety and Efficacy of Intravenous JNJ-64179375 Versus Oral Apixaban in Participants Undergoing Elective Total Knee Replacement Surgery (NCT03251482), a randomized phase 2 study. The primary outcome is Number of Participants With Treatment-emergent Bleeding Events (Clinical Events Committee [CEC]- Adjudicated).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03251482 |
| Phase | Phase 2 |
| Condition | VTE Prophylaxis With Anticoagulation After Total Knee Replacement Surgery |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 308 |
| Arms in the primary outcome | 5 |
| Lead sponsor | Janssen Research & Development, LLC |
| Results posted | Yes |
2. Clinical Question
Population
Participants undergoing elective total knee replacement surgery, in a study of anticoagulation for venous thromboembolism prophylaxis. The primary safety analysis included randomized participants who received at least one dose, partial or complete, of active study drug.
Intervention
Intravenous JNJ-64179375 was studied through dose escalation in Part 1 and dose-response assessment in Part 2. The posted primary-result arms include 0.3, 0.6, 1.2, and 1.8 mg/kg, each with apixaban placebo.
Comparator
The primary-result comparison group received oral apixaban 2.5 mg and intravenous JNJ-64179375 placebo. Part 1 descriptions also specify matched placebo and apixaban dosing, while the Part 2 descriptions list apixaban twice a day for 10 to 14 days.
Primary question
How many participants experienced a treatment-emergent bleeding event through Day 10 to 14 in each posted arm? The event composite included major, clinically relevant nonmajor, and minimal bleeding events adjudicated by a Clinical Events Committee. Part 2 also had an efficacy dose-response purpose concerning total venous thromboembolism, but the posted primary outcome is bleeding.
3. Trial Design
The registry identifies this as a randomized, double-blind, double-dummy, multicenter, parallel phase 2 study. Enrollment is listed as 308, and the record marks the study completed. The study had two parts: dose escalation in Part 1 and dose-response assessment in Part 2. The registry record does not report the allocation ratio or the operational details of the adaptive design.
In Part 1, the described dose cohorts included JNJ-64179375 at 0.3, 0.6, and 1.2 mg/kg, with optional additional cohorts. The posted primary-result arms also include 1.8 mg/kg. Active JNJ-64179375 was administered as a single intravenous dose on Day 1; matching placebo was used for blinding. The descriptions specify apixaban 2.5 mg orally twice a day, or matching apixaban placebo, for 10 to 14 days. In Part 2, four JNJ-64179375 dose groups were to be determined after review of Part 1 data, alongside an apixaban comparator group.
The primary-result safety population is described as randomized participants who received at least one dose, partial or complete, of active study drug. This is not necessarily identical to every participant enrolled or randomized. The number included in each reported arm is available with the outcome counts, but the registry record does not report the number randomized overall by part or a separate flow of participants through the study.
The study began on 2017-11-13, and primary completion is recorded as 2018-11-05. The registry record does not give detailed adaptive decision rules, the planned sample size for each part, or the rationale used to select the Part 2 doses.
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 planned to be conducted in 2 parts: Part 1 (Dose- Escalation) and Part 2 (Dose-Response). After completion of Part 1, the sponsor made the decision to not move forward with Part 2 as there was sufficient data to make a determination of efficacy in Part 1. Part 2 was not conducted, hence endpoints for Part 2 are not reported.
Overall Study
| Stage | JNJ-64179375 0.3 mg/kg and Apixaban Placebo | JNJ-64179375 0.6 mg/kg and Apixaban Placebo | JNJ-64179375 1.2 mg/kg and Apixaban Placebo | JNJ-64179375 1.8 mg/kg and Apixaban Placebo | Apixaban 2.5 mg and JNJ-64179375 Placebo IV |
|---|---|---|---|---|---|
| STARTED | 39 | 41 | 43 | 122 | 63 |
| Treated | 38 | 40 | 42 | 122 | 63 |
| COMPLETED | 39 | 40 | 43 | 122 | 63 |
| NOT COMPLETED | 0 | 1 | 0 | 0 | 0 |
Reasons for not completing this period:
| Reason | JNJ-64179375 0.3 mg/kg and Apixaban Placebo | JNJ-64179375 0.6 mg/kg and Apixaban Placebo | JNJ-64179375 1.2 mg/kg and Apixaban Placebo | JNJ-64179375 1.8 mg/kg and Apixaban Placebo | Apixaban 2.5 mg and JNJ-64179375 Placebo IV |
|---|---|---|---|---|---|
| Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Safety Analysis set included all randomized participants who received at least 1 dose (partial or complete) of active study drug (JNJ-64179375 or apixaban).
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: Safety analysis set included all randomized participants who received at least 1 dose (partial or complete) of active study drug (JNJ-64179375 or apixaban).
| Characteristic | Unit | JNJ-64179375 0.3 mg/kg and Apixaban Placebo | JNJ-64179375 0.6 mg/kg and Apixaban Placebo | JNJ-64179375 1.2 mg/kg and Apixaban Placebo | JNJ-64179375 1.8 mg/kg and Apixaban Placebo | Apixaban 2.5 mg and JNJ-64179375 Placebo IV | Total |
|---|---|---|---|---|---|---|---|
| Participants analysed | 38 | 40 | 42 | 122 | 63 | 305 | |
| Age, Continuous | years | 66.2 (SD 7.53) | 65.8 (SD 8.14) | 66.9 (SD 6.41) | 67.2 (SD 8.84) | 65.1 (SD 7.01) | 66.4 (SD 7.92) |
| Sex: Female, Male: Female | Participants | 21 | 25 | 35 | 99 | 42 | 222 |
| Sex: Female, Male: Male | Participants | 17 | 15 | 7 | 23 | 21 | 83 |
| Race/Ethnicity, Customized: Asian | Participants | 0 | 0 | 2 | 9 | 5 | 16 |
| Race/Ethnicity, Customized: Black | Participants | 1 | 0 | 0 | 1 | 1 | 3 |
| Race/Ethnicity, Customized: White | Participants | 36 | 39 | 39 | 110 | 54 | 278 |
| Race/Ethnicity, Customized: Unspecified | Participants | 1 | 1 | 1 | 2 | 3 | 8 |
| Region of Enrollment: Argentina | Participants | 2 | 4 | 3 | 8 | 10 | 27 |
| Region of Enrollment: Belgium | Participants | 5 | 3 | 3 | 2 | 3 | 16 |
| Region of Enrollment: Bulgaria | Participants | 0 | 0 | 0 | 2 | 0 | 2 |
| Region of Enrollment: Canada | Participants | 0 | 0 | 0 | 3 | 0 | 3 |
| Region of Enrollment: Italy | Participants | 0 | 1 | 0 | 5 | 2 | 8 |
| Region of Enrollment: Japan | Participants | 0 | 0 | 2 | 5 | 5 | 12 |
| Region of Enrollment: Latvia | Participants | 0 | 0 | 0 | 8 | 4 | 12 |
| Region of Enrollment: Lithuania | Participants | 0 | 0 | 3 | 8 | 1 | 12 |
| Region of Enrollment: Malaysia | Participants | 0 | 0 | 0 | 4 | 0 | 4 |
| Region of Enrollment: Poland | Participants | 17 | 9 | 4 | 18 | 12 | 60 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Treatment-emergent Bleeding Events (Clinical Events Committee [CEC]- Adjudicated), measured over Up to Day 10 to 14 (visit observation period).
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint counts participants with at least one treatment-emergent bleeding event adjudicated by a Clinical Events Committee. Its composite includes major bleeding, clinically relevant nonmajor bleeding, and minimal bleeding, assessed through Day 10 to 14. The event is counted at the participant level; the outcome is not a count of every separate bleeding episode.
A composite endpoint can capture several types of clinically relevant events within a defined observation period. In this study, the broad composite was the primary safety and tolerability measure used in Part 1 to inform dose selection. It provides a way to describe bleeding experience across the dose groups, while the individual components remain important because major, clinically relevant nonmajor, and minimal events differ in meaning. The registry record lists additional outcomes that separate some of these categories.
The endpoint is a safety outcome, not a direct measure of prevention of venous thromboembolism. The brief study description states that Part 2 was intended to assess the efficacy dose response for prevention of total venous thromboembolism, including deep vein thrombosis, nonfatal pulmonary embolism, or any death. However, the posted primary outcome being interpreted is bleeding. Its short, postoperative observation window also means it describes events during the specified period rather than long-term safety.
The registry record does not report a prespecified statistical method for the primary endpoint, nor does it provide a separate definition of treatment-emergent beyond the stated assessment window and adjudicated event composite.
7. Results Posted in the Registry
- JNJ-64179375 0.6 mg/kg and Apixaban Placebo: 0.0% (0/40) versus 5.3% (2/38) on control; risk difference -5.3 percentage points (95% CI -12.4 to 1.8); unadjusted two-proportion z-test p = 0.142.
- JNJ-64179375 1.2 mg/kg and Apixaban Placebo: 11.9% (5/42) versus 5.3% (2/38) on control; risk difference 6.6 percentage points (95% CI -5.5 to 18.7), risk ratio 2.26 (0.47–10.98); unadjusted two-proportion z-test p = 0.294.
- JNJ-64179375 1.8 mg/kg and Apixaban Placebo: 0.8% (1/122) versus 5.3% (2/38) on control; risk difference -4.4 percentage points (95% CI -11.7 to 2.8), risk ratio 0.16 (0.01–1.67); unadjusted two-proportion z-test p = 0.078.
- Apixaban 2.5 mg and JNJ-64179375 Placebo IV: 6.3% (4/63) versus 5.3% (2/38) on control; risk difference 1.1 percentage points (95% CI -8.2 to 10.4), risk ratio 1.21 (0.23–6.27); unadjusted two-proportion z-test p = 0.823.
Risk difference: JNJ-64179375 0.6 mg/kg and Apixaban Placebo
95% CI: -12.4 to 1.8 percentage points
Recalculated from the posted summary statistics
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.
| Secondary outcome | Type | Effect measure | Estimate (95% CI) | Planning size, 80% power |
|---|---|---|---|---|
| Number of Participants With Composite of Major and CRNM Bleeding Events (CEC-adjudicated) | Binary Endpoint | Risk difference | -2.6 pts (-7.7 to 2.5) | n/a |
| Number of Participants With Clinically Relevant Non-major (CRNM) Bleeding Events (CEC-adjudicated) | Binary Endpoint | Risk difference | -2.6 pts (-7.7 to 2.5) | n/a |
| Number of Participants With Major Bleeding or CRNM Bleeding Events (CEC-adjudicated) | Binary Endpoint | Risk difference | -2.6 pts (-7.7 to 2.5) | n/a |
Number of Participants With Composite of Major and CRNM Bleeding Events (CEC-adjudicated)
- 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:
- JNJ-64179375 0.6 mg/kg and Apixaban Placebo: 0.0% (0/40) versus 2.6% (1/38) on control; risk difference -2.6 percentage points (95% CI -7.7 to 2.5); unadjusted two-proportion z-test p = 0.302.
- JNJ-64179375 1.2 mg/kg and Apixaban Placebo: 4.8% (2/42) versus 2.6% (1/38) on control; risk difference 2.1 percentage points (95% CI -6.1 to 10.3), risk ratio 1.81 (0.17–19.16); unadjusted two-proportion z-test p = 0.616.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between JNJ-64179375 0.6 mg/kg and Apixaban Placebo and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between JNJ-64179375 1.2 mg/kg and Apixaban Placebo and the control. The interval gives the range of effects that remain compatible with the data.
Number of Participants With Clinically Relevant Non-major (CRNM) Bleeding Events (CEC-adjudicated)
- 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:
- JNJ-64179375 0.6 mg/kg and Apixaban Placebo: 0.0% (0/40) versus 2.6% (1/38) on control; risk difference -2.6 percentage points (95% CI -7.7 to 2.5); unadjusted two-proportion z-test p = 0.302.
- JNJ-64179375 1.2 mg/kg and Apixaban Placebo: 4.8% (2/42) versus 2.6% (1/38) on control; risk difference 2.1 percentage points (95% CI -6.1 to 10.3), risk ratio 1.81 (0.17–19.16); unadjusted two-proportion z-test p = 0.616.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between JNJ-64179375 0.6 mg/kg and Apixaban Placebo and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between JNJ-64179375 1.2 mg/kg and Apixaban Placebo and the control. The interval gives the range of effects that remain compatible with the data.
Number of Participants With Major Bleeding or CRNM Bleeding Events (CEC-adjudicated)
- 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:
- JNJ-64179375 0.6 mg/kg and Apixaban Placebo: 0.0% (0/40) versus 2.6% (1/38) on control; risk difference -2.6 percentage points (95% CI -7.7 to 2.5); unadjusted two-proportion z-test p = 0.302.
- JNJ-64179375 1.2 mg/kg and Apixaban Placebo: 4.8% (2/42) versus 2.6% (1/38) on control; risk difference 2.1 percentage points (95% CI -6.1 to 10.3), risk ratio 1.81 (0.17–19.16); unadjusted two-proportion z-test p = 0.616.
- Interpretation:
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between JNJ-64179375 0.6 mg/kg and Apixaban Placebo and the control. The interval gives the range of effects that remain compatible with the data.
- The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between JNJ-64179375 1.2 mg/kg and Apixaban Placebo and the control. The interval gives the range of effects that remain compatible with the data.
The registry record lists additional bleeding outcomes, including a composite of major and clinically relevant nonmajor bleeding, clinically relevant nonmajor bleeding, and major or clinically relevant nonmajor bleeding. In the detailed posted counts for these outcomes, events are also sparse. Across the arms, the pattern is broadly consistent with the primary composite’s small event totals, but these endpoints overlap conceptually and should not be treated as independent confirmations.
The secondary outcomes provide a more specific view of components of the broader bleeding composite. They can help distinguish whether the overall count reflects major events, clinically relevant nonmajor events, or a broader definition that also includes minimal bleeding. The detailed counts in the record do not establish a distinct comparative pattern across doses. Because the secondary endpoints are related to the primary endpoint, repeated testing of them does not create independent evidence of a treatment difference.
The registry lists 11 secondary outcomes, while detailed results and comparisons in the record cover only some of them. The registry record does not report the results for every listed secondary outcome in the information available for interpretation, nor does it provide a comprehensive analysis plan linking the endpoints. No conclusions about unreported outcomes should be inferred from the bleeding counts.
Secondary results generally carry less weight than a prespecified primary analysis because they may involve more comparisons, can be exploratory, and may not have the same protection against chance findings. Here, the registry record does not report a multiplicity adjustment or a hierarchy of secondary hypotheses. The available secondary counts should therefore be read as descriptive context for the primary safety result, not as separate proof that one regimen differs from another.
The stated Part 2 efficacy question concerned total venous thromboembolism, but the secondary bleeding outcomes do not answer that efficacy question. Keeping safety and efficacy outcomes distinct is essential when interpreting the overall pattern.
Secondary outcomes registered for this trial, for reference (only those above were recalculated):
- Number of Participants With Composite of Major and CRNM Bleeding Events (CEC-adjudicated)
- Number of Participants With Major Bleeding Event (CEC-adjudicated)
- Number of Participants With Clinically Relevant Non-major (CRNM) Bleeding Events (CEC-adjudicated)
- Number of Participants With Major Bleeding or CRNM Bleeding Events (CEC-adjudicated)
- Number of Participants With Minimal Bleeding Events (CEC-adjudicated)
- Number of Participants With Major VTE (CEC-adjudicated)
- Number of Participants With Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)
- Number of Participants With Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)
9. Statistical Interpretation
The posted primary outcome is sparse in every arm. The recorded counts are 2 participants among 38.0 receiving JNJ-64179375 0.3 mg/kg, 0 among 40.0 receiving 0.6 mg/kg, 5 among 42.0 receiving 1.2 mg/kg, 1 among 122.0 receiving 1.8 mg/kg, and 4 among 63.0 receiving apixaban 2.5 mg with intravenous placebo. These are observed counts in the safety analysis, not estimates of what would occur in a larger or different population.
The unadjusted risk-difference comparisons use the 0.3 mg/kg arm as the reference. For 0.6 mg/kg, the posted estimate is -0.053 with p = 0.142; for 1.2 mg/kg, it is 0.066 with p = 0.294; for 1.8 mg/kg, it is -0.044 with p = 0.078; and for apixaban, it is 0.011 with p = 0.823. Each corresponding confidence interval includes no difference. The direction of the estimates is not consistent across the JNJ-64179375 doses, and the small event counts make the comparisons imprecise.
These results do not establish that one arm has a higher or lower bleeding risk than another. A p-value above a conventional significance threshold is not evidence that the groups are equivalent; a confidence interval that includes no difference is compatible with a range of effects in either direction. The estimates also do not substitute for the sponsor’s planned analysis, whose method is not reported in the registry record.
The design included dose escalation and dose-response objectives, but the primary result alone does not show a clear monotonic dose pattern: the observed counts vary across arms, and the group sizes differ. It would be inappropriate to infer a dose-response relationship from these sparse counts without the full planned analysis and context for the adaptive design. Part 2’s stated efficacy objective concerned total venous thromboembolism, whereas this primary result measures bleeding; the two questions should not be conflated.
Overall, the posted data describe few adjudicated bleeding events during the short observation period. They are most useful as a record of what was observed in the studied groups, rather than as a precise basis for ranking doses or establishing comparative safety.
10. Statistical Methods Explained
The reported outcome is binary at the participant level: each participant either had a qualifying bleeding event during the observation period or did not. General: a risk is the proportion of participants with the event in a group. A risk difference contrasts two such proportions, expressing the absolute difference between groups. Negative values indicate a lower observed event proportion in the comparison arm than in the reference arm; positive values indicate a higher one. These directions describe the estimate, not proof of a treatment effect.
How to read the comparisons
The reference group for the posted comparisons is JNJ-64179375 0.3 mg/kg with apixaban placebo. Each other arm is contrasted with that group using an unadjusted risk difference. For the 0.6 mg/kg arm, no event was recorded, compared with 2 in the reference group; for the 1.2 mg/kg arm, the recorded count was 5 compared with 2; for the 1.8 mg/kg arm, it was 1 compared with 2; and for apixaban, it was 4 compared with 2. Group sizes differ, so comparing raw counts alone would not account for the number of participants at risk. The posted risk differences use the group-specific proportions.
The p-values listed for these comparisons are unadjusted. They assess how compatible the observed contrast is with a specified no-difference model under the calculation used; they do not measure the probability that the no-difference model is true, nor do they state the size or clinical importance of an effect. The registry record does not report the sponsor’s statistical test, any covariate adjustment, or a prespecified hypothesis-testing procedure. Therefore, the unadjusted comparisons should be read as descriptive statistical contrasts, not assumed to be the trial’s complete confirmatory analysis.
Confidence intervals and sparse events
General: a confidence interval describes uncertainty around an estimate under a statistical model. A narrow interval indicates greater precision, while a wide interval indicates that a broad range of values remains compatible with the data. For these comparisons, every interval includes no risk difference. That means the posted data do not rule out no difference, and they also leave room for differences in either direction. Small event counts make this uncertainty particularly important: a small change in the number of events can materially change a proportion and its contrast.
The record reports a risk ratio and odds ratio for some comparisons, but not for the 0.6 mg/kg comparison. Ratios compare relative rather than absolute event frequencies. With very few events, relative measures can be unstable and their intervals can be broad; they should not be treated as more definitive than the risk differences. No adjusted estimates are reported.
What the planning illustrations mean
The planning illustrations use the observed effect and explore sample sizes for 80% and 90% power under the listed assumptions: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Rows describe planning for 100%, 75%, or 50% of the observed effect. These are hypothetical planning calculations, not observed power and not the trial’s documented sample-size plan. The registry record does not report the trial’s own sample-size justification or whether those planning assumptions match its design.
The illustrations are especially sensitive when the observed difference comes from very few events. A small observed contrast can imply a large planning requirement, while the calculation does not resolve whether the observed contrast is a stable estimate of the effect worth detecting. They should be interpreted as scenarios conditional on their assumptions, not as evidence that the study was adequately or inadequately powered.
Analysis population and design context
The primary outcome uses a safety analysis set defined by receipt of at least one dose of active study drug after randomization. The posted arm denominators are those associated with this outcome. The registry record does not report a separate intention-to-treat analysis, missing-outcome counts, or a detailed account of participants excluded from the safety set. Randomization and blinding are features of the design, but the result should still be interpreted according to the stated analysis population and the information actually reported.
The adaptive, two-part structure is relevant because Part 1 included dose escalation and dose selection, and Part 2 was intended to assess dose response. However, the registry record does not describe interim analyses, dose-selection rules, or how any design adaptations were incorporated into the final statistical analysis. Without those details, the displayed unadjusted contrasts cannot be assumed to account for design adaptations or multiple testing.
11. Confidence Intervals and Precision
The risk-difference confidence intervals for each posted primary comparison include no difference. In practical terms, the data are compatible with no contrast as well as with effects in either direction. The intervals do not support a precise ranking of the JNJ-64179375 doses against the 0.3 mg/kg reference group or a precise comparison with apixaban.
Precision is limited by the small number of observed primary events in the arms, rather than by the enrollment figure alone. The group denominators vary, from 38.0 in the reference arm to 122.0 in the 1.8 mg/kg arm, and the event counts are low throughout. When events are rare, even a modest change in the observed count can shift the estimated group proportion and risk difference. Unequal group sizes also mean that the amount of information is not the same across comparisons.
General: a confidence interval is not a guarantee that the true effect lies within its endpoints. It summarizes uncertainty under the method used to construct it. The registry record does not identify the interval method or confidence level, so the intervals should be interpreted as posted estimates rather than attributed to a particular method not documented in the record.
The unadjusted p-values do not remove this uncertainty. They address compatibility with a no-difference hypothesis under a test, while the confidence intervals convey a range of plausible contrasts. Neither measure makes a sparse result precise. The registry record also does not report adjusted intervals that account for the multiple dose comparisons or the adaptive two-part design.
Accordingly, the main precision message is not that the groups are alike, but that the posted data leave substantial uncertainty about differences in bleeding risk. The point estimates are descriptions of the observed sample, and the intervals caution against treating them as stable estimates for broader populations.
12. Multiplicity, Missing Data and Analysis Populations
The posted primary comparisons contrast four arms with the 0.3 mg/kg reference group. The registry record does not report whether these comparisons were prespecified as a family, whether a multiplicity procedure was planned, or whether any adjustment was applied. The listed p-values are unadjusted. When several doses and outcomes are compared, the chance of at least one apparently unusual result can increase; general statistical practice therefore distinguishes exploratory unadjusted comparisons from results controlled for multiple testing.
The study’s adaptive design makes the missing analysis details particularly relevant. Part 1 involved dose escalation and selection of doses for Part 2, while the Part 2 doses were to be determined after reviewing Part 1 data. The record does not report the dose-selection rules, interim analyses, adaptations actually made, or the statistical method used to account for any adaptation. It would be speculative to assume a particular approach.
The safety analysis population is defined as all randomized participants who received at least one dose, partial or complete, of active study drug. The record does not report how many randomized participants did not meet this definition, whether any primary endpoint data were missing, or how missing data were handled. It also does not report a separate intention-to-treat result. These omissions limit assessment of how the analysis population relates to randomization and whether exclusions could affect the comparisons.
The primary endpoint was adjudicated by a Clinical Events Committee, but the registry record does not provide details of the adjudication process or report a statistical analysis plan. It also does not describe any adjustment for baseline factors, stratification factors, or differences between study parts. The reported comparisons should therefore be treated as unadjusted summaries rather than assumed to reflect a fully specified confirmatory model.
The record identifies a planned efficacy dose-response purpose for Part 2 but the primary posted outcome is a safety endpoint. It does not provide enough analysis detail to determine how safety and efficacy objectives were integrated or prioritized in the final inferential framework.
13. 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 |
|---|---|---|---|
| JNJ-64179375 0.3 mg/kg and Apixaban Placebo | 2 | 38 | 5.3% |
| JNJ-64179375 0.6 mg/kg and Apixaban Placebo | 2 | 40 | 5.0% |
| JNJ-64179375 1.2 mg/kg and Apixaban Placebo | 4 | 42 | 9.5% |
| JNJ-64179375 1.8 mg/kg and Apixaban Placebo | 13 | 122 | 10.7% |
| Apixaban 2.5 mg and JNJ-64179375 Placebo IV | 5 | 63 | 7.9% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| JNJ-64179375 0.3 mg/kg and Apixaban Placebo | 0 of 38 |
| JNJ-64179375 0.6 mg/kg and Apixaban Placebo | 0 of 40 |
| JNJ-64179375 1.2 mg/kg and Apixaban Placebo | 0 of 42 |
| JNJ-64179375 1.8 mg/kg and Apixaban Placebo | 0 of 122 |
| Apixaban 2.5 mg and JNJ-64179375 Placebo IV | 0 of 63 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 2% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| JNJ-64179375 0.3 mg/kg and Apixaban Placebo | 19 of 38 |
| JNJ-64179375 0.6 mg/kg and Apixaban Placebo | 17 of 40 |
| JNJ-64179375 1.2 mg/kg and Apixaban Placebo | 26 of 42 |
| JNJ-64179375 1.8 mg/kg and Apixaban Placebo | 37 of 122 |
| Apixaban 2.5 mg and JNJ-64179375 Placebo IV | 20 of 63 |
Most frequent serious adverse event terms
| Event term | Organ system | JNJ-64179375 0.3 mg/kg and Apixaban Placebo | JNJ-64179375 0.6 mg/kg and Apixaban Placebo | JNJ-64179375 1.2 mg/kg and Apixaban Placebo | JNJ-64179375 1.8 mg/kg and Apixaban Placebo | Apixaban 2.5 mg and JNJ-64179375 Placebo IV |
|---|---|---|---|---|---|---|
| Deep Vein Thrombosis | Vascular disorders | 0 of 38 | 0 of 40 | 1 of 42 | 6 of 122 | 0 of 63 |
| Angina Unstable | Cardiac disorders | 0 of 38 | 0 of 40 | 0 of 42 | 1 of 122 | 0 of 63 |
| Primary Hyperaldosteronism | Endocrine disorders | 0 of 38 | 0 of 40 | 0 of 42 | 1 of 122 | 0 of 63 |
| Ascites | Gastrointestinal disorders | 0 of 38 | 0 of 40 | 0 of 42 | 0 of 122 | 1 of 63 |
| Impaired Healing | General disorders | 0 of 38 | 0 of 40 | 1 of 42 | 0 of 122 | 0 of 63 |
| Oedema Peripheral | General disorders | 0 of 38 | 0 of 40 | 0 of 42 | 0 of 122 | 1 of 63 |
| Peripheral Swelling | General disorders | 0 of 38 | 1 of 40 | 0 of 42 | 0 of 122 | 0 of 63 |
| Pyrexia | General disorders | 0 of 38 | 0 of 40 | 0 of 42 | 0 of 122 | 1 of 63 |
| Herpes Zoster | Infections and infestations | 0 of 38 | 0 of 40 | 0 of 42 | 1 of 122 | 0 of 63 |
| Infection | Infections and infestations | 0 of 38 | 0 of 40 | 1 of 42 | 0 of 122 | 0 of 63 |
Most frequent non-serious adverse event terms
| Event term | Organ system | JNJ-64179375 0.3 mg/kg and Apixaban Placebo | JNJ-64179375 0.6 mg/kg and Apixaban Placebo | JNJ-64179375 1.2 mg/kg and Apixaban Placebo | JNJ-64179375 1.8 mg/kg and Apixaban Placebo | Apixaban 2.5 mg and JNJ-64179375 Placebo IV |
|---|---|---|---|---|---|---|
| Pyrexia | General disorders | 6 of 38 | 0 of 40 | 0 of 42 | 8 of 122 | 1 of 63 |
| Nausea | Gastrointestinal disorders | 1 of 38 | 3 of 40 | 5 of 42 | 3 of 122 | 0 of 63 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 1 of 38 | 0 of 40 | 5 of 42 | 3 of 122 | 0 of 63 |
| Deep Vein Thrombosis | Vascular disorders | 2 of 38 | 1 of 40 | 0 of 42 | 2 of 122 | 3 of 63 |
| Hypertension | Vascular disorders | 1 of 38 | 1 of 40 | 0 of 42 | 4 of 122 | 2 of 63 |
| Procedural Pain | Injury, poisoning and procedural complications | 0 of 38 | 0 of 40 | 1 of 42 | 4 of 122 | 2 of 63 |
| Diarrhoea | Gastrointestinal disorders | 1 of 38 | 2 of 40 | 0 of 42 | 2 of 122 | 1 of 63 |
| Vomiting | Gastrointestinal disorders | 0 of 38 | 1 of 40 | 2 of 42 | 3 of 122 | 0 of 63 |
| Constipation | Gastrointestinal disorders | 2 of 38 | 0 of 40 | 0 of 42 | 1 of 122 | 2 of 63 |
| Urinary Tract Infection | Infections and infestations | 0 of 38 | 0 of 40 | 3 of 42 | 1 of 122 | 1 of 63 |
Serious events with the highest arm-level rate: deep vein thrombosis (4.9%), overdose (2.6%), bloody discharge (2.6%), peripheral swelling (2.5%), arthralgia (2.5%).
The posted serious adverse event counts are 2 among 38 participants in the 0.3 mg/kg arm, 2 among 40 in the 0.6 mg/kg arm, 4 among 42 in the 1.2 mg/kg arm, 13 among 122 in the 1.8 mg/kg arm, and 5 among 63 in the apixaban arm. The record lists 0 deaths in each of these arms. These figures describe the recorded safety experience; they are not the same endpoint as the adjudicated primary bleeding composite.
The record also gives counts for participants with other adverse events, but those counts should not be combined with serious events or with the primary endpoint. The listed serious adverse event terms include deep vein thrombosis, overdose, bloody discharge, peripheral swelling, arthralgia, and impaired healing. The registry record does not provide enough context in these figures to determine whether an event was caused by study treatment.
Serious adverse event counts should be read alongside the arm sizes, observation period, and study population. Differences in counts alone do not establish a comparative safety effect, particularly when event numbers are limited and the registry record does not report an adjusted safety analysis. The absence of recorded deaths in these arms does not establish absence of other serious risks.
14. What the Result Does, and Does Not, Mean
The result establishes what the registry reports for the primary bleeding endpoint during the stated observation period: a small number of participants in each arm had an adjudicated treatment-emergent bleeding event, with counts ranging from none to 5. The unadjusted risk-difference intervals all include no difference, and the p-values do not provide evidence of a clear separation between the reference and comparison arms.
It does not establish that the treatments or doses are equivalent. Equivalence requires a defined margin and an analysis designed to assess it; neither is reported in the registry record. Nor does a nonsignificant unadjusted comparison show that clinically meaningful differences are absent. The intervals remain compatible with differences in either direction, reflecting limited precision.
It also does not prove that a particular dose is safer, that bleeding risk rises or falls with dose, or that apixaban and JNJ-64179375 have the same safety profile. The event counts do not show a consistent direction across the JNJ-64179375 dose arms, and the trial’s adaptive dose-selection details are not reported. A descriptive pattern should not be mistaken for a demonstrated dose response.
The primary outcome measures bleeding, not prevention of venous thromboembolism. The registry description identifies total venous thromboembolism as an efficacy objective for Part 2, but the posted primary result alone cannot establish an efficacy conclusion. The record also does not report a complete efficacy analysis in the details.
Finally, the findings apply to the study’s defined setting: participants undergoing elective total knee replacement and a short assessment through Day 10 to 14. They do not by themselves determine outcomes in other populations, procedures, follow-up periods, or treatment contexts. These limitations frame the result as a sparse, short-term safety description rather than a definitive treatment comparison.
15. Why This Trial Matters Statistically
This study illustrates why a randomized, blinded design does not automatically yield a precise answer when the endpoint is uncommon. The arms had different denominators, but only a few primary bleeding events were recorded. The resulting risk differences and confidence intervals are more informative when read together: point estimates give direction and scale, while intervals convey that considerable uncertainty remains.
The trial also connects two statistical aims that are often difficult to interpret together. Part 1 was designed around dose escalation, safety, tolerability, and selection of doses; Part 2 was intended to evaluate dose response for venous thromboembolism prevention. The posted primary endpoint is a bleeding composite. Understanding how those objectives, the dose adaptations, and the final analyses fit together would require details not reported in the registry record.
For clinical researchers, the comparison highlights the importance of distinguishing a planned design from a post hoc planning illustration. The posted sample-size scenarios are conditional calculations based on observed effects and specified assumptions; they are not the study’s documented sample-size rationale or observed power. This distinction prevents a descriptive planning exercise from being mistaken for an assessment of the trial’s original design.
The sparse counts also show why an unadjusted p-value should not be treated as a standalone verdict. Confidence intervals, endpoint definition, analysis population, multiplicity, and study design all contribute to interpretation. When several dose and outcome comparisons are available, clear reporting of the analysis hierarchy and adaptation rules is essential for readers to judge the strength of evidence.
16. 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 covers events through Day 10 to 14, so these results do not describe longer-term bleeding experience. The study population is limited to participants undergoing elective total knee replacement surgery, and the registry record does not support extending the findings to other clinical settings.
The primary endpoint is a composite that combines major, clinically relevant nonmajor, and minimal bleeding. A composite can summarize event experience, but its overall count may conceal differences among components. Although the record lists related secondary bleeding outcomes, detailed results are not available for every listed secondary outcome. Sparse event counts further limit conclusions about individual event categories.
The study had an adaptive dose-escalation and dose-response structure, yet the registry record does not describe its decision rules, interim analyses, or which adaptations were implemented. Without those details, it is not possible to assess how dose selection may affect interpretation of the posted comparisons. The record also does not report the sponsor’s full statistical plan, prespecified multiplicity handling, or detailed missing-data procedures.
The safety analysis includes randomized participants who received at least one dose of active study drug. The registry record does not provide a participant flow or a separate intention-to-treat analysis, so the relationship between this safety set and all randomized participants cannot be fully assessed. The posted arm sizes are unequal, and the number of primary events is small, limiting the precision of comparative estimates.
Finally, the registry record does not report a detailed efficacy analysis for the stated Part 2 venous thromboembolism objective in the registry record. The primary bleeding result therefore cannot be used as a substitute for an efficacy assessment.
17. Related Tutorials
18. Related Statistical Calculators
19. Sources
- ClinicalTrials.gov: A Study to Evaluate the Safety and Efficacy of Intravenous JNJ-64179375 Versus Oral Apixaban in Participants Undergoing Elective Total Knee Replacement Surgery — NCT03251482.
- Registry record last updated 2019-11-25; status last verified 2019-11.
- Results first posted 2019-11-25.
- 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.
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20. Record Summary
NCT03251482 is a completed randomized, double-blind, double-dummy, multicenter, parallel phase 2 study of intravenous JNJ-64179375 and oral apixaban in participants undergoing elective total knee replacement surgery. Enrollment is listed as 308. The design included Part 1 dose escalation and Part 2 dose-response assessment.
The posted primary endpoint counts participants with a Clinical Events Committee-adjudicated treatment-emergent bleeding event through Day 10 to 14. Observed counts are low across all five reported arms, and all posted unadjusted risk-difference confidence intervals include no difference. These results are imprecise and do not establish equivalence, a dose-response pattern, or comparative efficacy.
The registry describes a Part 2 efficacy objective involving total venous thromboembolism, but the primary result is a bleeding outcome. Details of the adaptive rules, multiplicity procedures, missing-data handling, and full statistical analysis plan are not reported in the registry record.