EINSTEIN Junior Phase II: Oral Rivaroxaban in Young Children With Venous Thrombosis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for EINSTEIN Junior Phase II: Oral Rivaroxaban in Young Children With Venous Thrombosis (NCT02309411), a na phase 2 study. The primary outcome is Number of Subjects With Major Bleeding and Clinically Relevant Non-Major Bleeding Events.

2. Clinical Question

The study addressed use of oral rivaroxaban in young children with various manifestations of venous thrombosis. Its stated purpose included assessing safety through the incidence and types of bleeding events, checking for worsening of blood clots, and characterizing how long rivaroxaban stays in the body.

The primary endpoint combines major bleeding with clinically relevant non-major bleeding. It is a participant count, rather than a measure of the amount of bleeding or a time-to-event estimate. The registry describes additional outcomes covering symptomatic recurrent venous thromboembolism, asymptomatic deterioration in thrombotic burden on repeat imaging, changes in clotting tests, and plasma rivaroxaban concentration.

The question is therefore primarily descriptive: what safety and pharmacologic observations were recorded during this short treatment period? Because the design is single-group and the registry warns against treating the listed comparator groups as like-for-like controls, the record does not support interpreting the data as a randomized estimate of a treatment difference.

3. Trial Design

This was a phase II, single-group study, with allocation recorded as not applicable and masking recorded as none. The registry lists enrollment as 46 and the status as completed. The study started on 2015-01-15, and primary completion was recorded as 2017-04-05. Its official title describes a 30-day study in young children with various manifestations of venous thrombosis.

Participants received oral rivaroxaban using dosing adjusted for age and body weight. The stated dosing objective was to achieve exposure similar to that observed in adults treated for venous thromboembolism with 20 mg rivaroxaban once daily. This is a pharmacokinetic target described in the record; it does not establish that a particular exposure was achieved for every participant.

The primary safety outcome covered major bleeding and clinically relevant non-major bleeding during treatment or within 2 days after treatment stopped, up to 32 days. The registry also lists outcomes involving recurrent or worsening thrombosis, prothrombin time, activated partial thromboplastin time, and rivaroxaban plasma concentration.

Although the adverse-event record includes groups labeled rivaroxaban and anticoagulant comparator, the registry expressly notes that the study is not a randomized comparison and that the arms are not a like-for-like control comparison. The presence of comparator-labeled safety data therefore does not change the stated single-group design or provide a basis for a causal treatment contrast. The registry record does not report further details of a statistical analysis plan, including a planned method for adjusting comparisons or estimating treatment effects.

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: Overall, 51 subjects were screened, of these 5 subjects were screen failures; 4 subjects withdrew from study and 1 subject failed screening. Total of 46 subjects were assigned to treatment with 6 subjects received anticoagulant comparator (standard of care) and 40 subjects received rivaroxaban.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: SAF included all subjects who received at least one dose of the study medication.

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Major Bleeding and Clinically Relevant Non-Major Bleeding Events, measured over During or within 2 days after stop of study treatment (up to 32 days).

The primary endpoint counts participants with major bleeding or clinically relevant non-major bleeding during treatment or within 2 days after stopping treatment, up to 32 days. It combines events that differ in severity but share clinical importance. The endpoint is a count of participants meeting either definition, not a count of all bleeding episodes.

Major bleeding is defined as overt bleeding associated with a fall in hemoglobin of 2 g/dL or more; bleeding leading to transfusion of the equivalent of 2 or more units of packed red blood cells or whole blood in adults; bleeding at a critical site; or bleeding contributing to death. The listed critical sites include intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, and retroperitoneal sites.

Clinically relevant non-major bleeding is overt bleeding that does not meet the major-bleeding criteria but is associated with medical intervention, unscheduled contact with a physician, temporary cessation of study treatment, discomfort for the child such as pain, or impairment of daily activities such as loss of school days or hospitalization.

Such a combined endpoint is used to capture bleeding with substantial clinical consequences while also including events that fall short of the major category but still prompt care or disrupt daily life. The registry record does not report the number of participants meeting this primary endpoint. It therefore does not permit a numerical description of the observed primary outcome or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical interpretation depends first on distinguishing the study design from the way adverse events are grouped in the registry. The design is recorded as single-group, with allocation not applicable and no masking. A comparator label within the adverse-event record does not by itself create a randomized comparison. The registry specifically warns that the listed arms are not a like-for-like control comparison.

What does a participant count represent?

The primary outcome is a count of participants who experienced either major bleeding or clinically relevant non-major bleeding under the endpoint definitions. A participant count is different from an event count: a person with more than one qualifying episode would still be counted as a participant for an outcome defined this way, unless the analysis specification states otherwise. The registry describes the measure as a participant count, but does not report additional rules for handling repeated episodes.

The primary endpoint has a defined observation window: during treatment or within 2 days after treatment stops, up to 32 days. A time window matters because an event outside the specified period would not necessarily qualify for this endpoint. The record does not report further details about event adjudication or how the end of observation was handled for participants with incomplete follow-up.

Why does a confidence interval matter?

General statistical explanation: a confidence interval expresses the uncertainty associated with an estimated quantity under a specified statistical model and sampling process. A count alone does not show how precisely the underlying event frequency has been estimated. For a single-group safety outcome, an interval around an event frequency can communicate uncertainty, but it does not create a comparison group or remove limitations from the design.

The registry record does not report a primary endpoint count, estimated event frequency, or confidence interval. It is therefore not possible to evaluate the precision of the primary bleeding estimate from the posted information. The group-level adverse-event counts can be read descriptively, but a reader should not treat them as a substitute for an interval around the primary endpoint.

Why is over-dispersion relevant?

General statistical explanation: over-dispersion occurs when observed variability is greater than a statistical model expects. It can matter for outcomes such as event counts, because a model that assumes too little variability may produce uncertainty estimates that are too narrow. The primary outcome in this record is a participant count, not an event-rate model with a reported dispersion estimate. The registry record does not report a dispersion parameter or a model-based analysis for the primary endpoint, so over-dispersion cannot be assessed as a feature of that analysis.

How should the adverse-event groups be read?

The serious and other adverse-event summaries give counts of affected participants within their respective listed groups. They do not provide a randomized treatment contrast. The comparator-labeled group is small in the posted record and is not described as randomized or comparable with the rivaroxaban groups. Differences between group counts could reflect differences in participant characteristics, care, observation, or other factors; the record does not report analyses that separate these possibilities.

General statistical explanation: a treatment comparison requires a design and analysis that make groups sufficiently comparable for the intended question. Random allocation is one way to support such comparability, but it is not recorded for this study. An unadjusted comparison of the listed adverse-event groups would therefore not establish a causal effect, even if a numerical difference were calculated. No such recalculation is presented in the registry record.

What can planning calculations say?

General statistical explanation: a sample-size calculation is a planning exercise about the information a future study might need to detect a specified effect under stated assumptions. It is not an estimate of what the completed study observed, and it is not observed power. The record describes any sample-size illustrations as based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the intended effect is a stated fraction of the observed effect. Such illustrations do not describe the trial's own design or establish that the study was planned with those assumptions. The registry record does not report a sample-size justification for the trial itself.

For time-to-event outcomes, a planning method may focus on the total number of events; for other outcomes, the record describes planning quantities as participants per arm for a stated power. These are general planning conventions, not observed results. They should not be interpreted as evidence that the study had a particular chance of finding an effect, and they do not supply the missing primary endpoint result.

Finally, the registry records no analyses for the outcome measures. It does not report an inferential method, model covariates, a confidence-interval method, or a multiplicity procedure. Without these details and without the primary endpoint result, a model-based interpretation cannot be reconstructed from the record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists several outcomes in addition to the primary bleeding endpoint. These include symptomatic recurrent venous thromboembolism, asymptomatic deterioration in thrombotic burden on repeat imaging, changes from baseline in prothrombin time and activated partial thromboplastin time, and plasma rivaroxaban concentration. Considering several outcomes raises the general issue of multiplicity: when many hypotheses are tested, the chance of at least one apparently unusual finding can increase if no adjustment or prioritization is used.

The registry record does not report a multiplicity procedure, a hierarchy for secondary outcomes, or a statistical analysis plan specifying which outcomes would be tested inferentially. It also records no outcome analyses. Thus, there is no reported basis for determining whether any secondary findings were adjusted for multiple testing or intended as descriptive measures.

The primary analysis population is described as SAF, including all subjects who received at least one dose of study medication. That definition identifies a treated safety population. The registry record does not report how missing outcome information was handled, whether any participants lacked endpoint follow-up, or whether any imputation or sensitivity analysis was used. It also does not report analysis-population definitions for the secondary outcomes.

These omissions matter because missing observations and analytic choices can affect the interpretation of event counts and uncertainty. The record does not support assumptions about why data might be missing, whether follow-up was complete, or how unobserved outcomes were treated. The posted safety counts can be read as the recorded summaries for the listed groups, but the record does not provide enough analysis detail to assess missing-data sensitivity or multiplicity-adjusted evidence.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: optic atrophy (16.7%), headache (16.7%), pyrexia (6.7%), respiratory disorder (6.7%).

The adverse-event record separates serious adverse events, other adverse events, and deaths. For the rivaroxaban BID suspension group labeled 2 - 6 Years, it records 0 of 25 affected by a serious adverse event and 14 of 25 affected by an other adverse event. For the group labeled 6 Months - 2 Years, it records 2 of 15 and 11 of 15, respectively. For the anticoagulant comparator group labeled 2 - 6 Years, it records 1 of 6 and 3 of 6. Deaths are recorded as 0 for each group.

These categories should not be conflated with the primary endpoint. The primary endpoint uses specified criteria for major bleeding and clinically relevant non-major bleeding; the adverse-event counts are broader categories. The record does not say that every serious adverse event was bleeding or that every other adverse event met the clinically relevant non-major bleeding definition.

The registry also lists serious adverse-event terms and percentages: optic atrophy and headache at 16.7% each, and pyrexia and respiratory disorder at 6.7% each. These entries are descriptive and do not, by themselves, establish cause. Since the study was not a randomized comparison and the registry says the arms are not like-for-like controls, group counts should not be read as comparative treatment effects.

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

The record establishes that a phase II, single-group study evaluated age- and body-weight-adjusted oral rivaroxaban in young children with venous thrombosis. It describes a safety focus on bleeding, as well as outcomes related to thrombosis, coagulation tests, and drug concentration. The posted adverse-event record gives group-level counts of serious events, other events, and deaths.

It does not establish the numerical result for the primary endpoint of major bleeding and clinically relevant non-major bleeding. That outcome is defined in detail, but its participant count is not reported in the registry record. The broader adverse-event categories cannot replace that missing endpoint result because the record does not show how those categories correspond to the primary definition.

The study design also limits interpretation. The trial is recorded as single-group, with allocation not applicable and no masking. Although the adverse-event record includes an anticoagulant comparator group, the registry warns that the arms are not a like-for-like control comparison. The counts therefore do not support a causal conclusion about differences between rivaroxaban and another treatment.

The dosing objective was to achieve exposure similar to that observed in adults treated for venous thromboembolism with 20 mg once daily. This objective describes the rationale for age- and body-weight-adjusted dosing; it does not demonstrate that exposure was achieved in every child. The record lists pharmacokinetic outcomes but does not report their numerical results in the registry record.

In short, the record describes the study question and some safety summaries, but does not provide the primary bleeding result or the analysis needed to estimate its precision. It should not be interpreted as showing that treatment does or does not work, or as establishing a comparative safety effect.

13. Why This Trial Matters Statistically

This study is statistically notable because it asks a safety and pharmacology question in a pediatric population using dosing adjusted for age and body weight. The target exposure was framed in relation to adults treated for venous thromboembolism with 20 mg rivaroxaban once daily. That makes the distinction between a dosing objective and an observed pharmacokinetic result important: the former is stated, while numerical pharmacokinetic findings are not reported in the registry record.

The primary endpoint also illustrates why definitions matter in safety studies. It combines major bleeding with clinically relevant non-major bleeding, using criteria that include both severity and consequences for care or daily activity. A participant count under such a definition can be clinically informative, but interpretation depends on the actual endpoint count, observation window, and analysis. The record gives the definition and timeframe but not the numerical primary result.

The study further illustrates the limits of descriptive comparator data. Adverse-event groups are listed for rivaroxaban and anticoagulants, but the registry identifies the design as single-group and warns that these are not like-for-like control arms. Statistical contrasts between such groups would be vulnerable to confounding and should not be treated as randomized evidence.

Finally, the record shows why completeness of reporting matters. No outcome analyses are recorded, and the primary endpoint result, missing-data approach, multiplicity plan, and detailed statistical methods are not reported. Readers can distinguish the design and recorded safety summaries, but cannot reconstruct an inferential analysis or evaluate the precision of the principal safety outcome from the registry record.

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 primary limitation for interpretation is that the registry record does not report a numerical result for the primary bleeding endpoint. Although the endpoint definition and observation window are detailed, there is no reported count or uncertainty estimate for participants meeting that definition. This prevents direct assessment of the principal safety outcome from the posted record.

The design is single-group, with allocation recorded as not applicable and masking as none. The adverse-event record includes an anticoagulant comparator group, but the registry explicitly cautions that the arms are not a like-for-like control comparison. These data therefore cannot establish a causal difference between treatments.

The safety groups are age-labeled and have different recorded group sizes. The registry record does not provide enough information to assess whether these groups were otherwise comparable, how participants were assigned to them, or whether the comparator data were collected under the same conditions. Counts should be interpreted descriptively.

The record lists outcomes related to thrombosis, coagulation tests, and pharmacokinetics, but does not report their numerical results in the registry record. It also does not report a statistical analysis plan, handling of missing data, multiplicity adjustment, or detailed methods for endpoint assessment. The primary population is defined as subjects receiving at least one dose, but further analysis-population details are not reported.

The record describes a 30-day study and gives an endpoint window of up to 32 days. Conclusions from that short observation period should not be extended to longer-term outcomes. These limitations leave the posted record useful for understanding the study's question and design, but insufficient for a complete statistical evaluation of its primary result.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: EINSTEIN Junior Phase II: Oral Rivaroxaban in Young Children With Venous Thrombosis — NCT02309411.
• Registry record last updated 2018-08-21; status last verified 2018-07.
• Results first posted 2018-06-13.
• 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.

18. Record Summary

NCT02309411 is a completed phase II study of oral rivaroxaban in young children with venous thrombosis. It is recorded as a single-group study with no masking and enrollment of 46. Dosing was adjusted for age and body weight, with the aim of achieving exposure similar to that observed in adults treated for venous thromboembolism with 20 mg once daily.

The primary outcome was the number of participants with major bleeding or clinically relevant non-major bleeding during treatment or within 2 days after stopping treatment, up to 32 days. The registry record does not report a numerical result for this endpoint. It lists other outcomes involving recurrent or worsening thrombosis, coagulation tests, and plasma drug concentration, but no outcome analyses are recorded.

Adverse-event summaries include rivaroxaban and anticoagulant comparator groups. The registry cautions that the study was not a randomized comparison and that the arms are not like-for-like controls. The posted group counts are therefore descriptive and do not establish a comparative treatment effect.