Rivaroxaban for Treatment in Venous or Arterial Thrombosis in Neonates: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Rivaroxaban for Treatment in Venous or Arterial Thrombosis in Neonates (NCT02564718), a na phase 1, phase 2 study. The primary outcome is Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Day 1.

2. Clinical Question

The study title describes a 7-day investigation of safety, efficacy, pharmacokinetic properties, and pharmacodynamic properties. Its primary outcome is specifically a measure of drug concentration, not a direct measure of clot improvement or bleeding. The registry summary also describes checking for bleeding events and worsening of blood clots. Secondary outcomes include the number of participants with major and clinically relevant non-major bleeding events, and the number with symptomatic recurrent venous thromboembolism or asymptomatic deterioration in thrombotic burden on repeat imaging.

Accordingly, the statistical question is principally descriptive: what Day 1 concentrations were observed, and what safety and thrombotic events were recorded during the study? The record does not report a comparator-based treatment effect. It also does not report the primary concentration results, so the magnitude and precision of the pharmacokinetic findings cannot be assessed from the registry record.

3. Trial Design

The registry identifies this as a completed Phase 1 and Phase 2 study with a single-group model. The listed enrollment is 10. The study began on 2015-11-19 and its primary completion date is 2017-12-18. The sponsor is Bayer. The trial record describes treatment with oral rivaroxaban suspension for children from birth to less than 6 months who had arterial or venous thrombosis.

The suspension was prepared from granules and dosed according to body weight as a 0.1% suspension (1 mg/mL). The adverse-event record separates participants into listings titled Rivaroxaban Suspension Bid and Rivaroxaban Suspension Tid. However, the record does not describe allocation to these schedules, and it explicitly indicates that the arms are not a like-for-like control comparison. Allocation is listed as NA and masking as none. The registry record does not report a randomized comparator.

The primary endpoint is plasma rivaroxaban concentration on Day 1, summarized as a geometric mean with geometric coefficient of variation. Its sampling windows are described separately for BID and TID dosing. The study summary also identifies safety assessment through bleeding events and checking for worsening of blood clots. The listed secondary outcomes concern major and clinically relevant non-major bleeding, symptomatic recurrent venous thromboembolism, and asymptomatic deterioration on repeat imaging.

The registry reports 12 outcome measures and 0 analyses. It does not report the full statistical analysis plan, the rationale for enrollment, or how participants were assigned to the BID and TID schedules. Therefore, the study design can be described from the registry record, but details beyond those descriptions are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Overall, 11 participants were screened, of these 1 participant was not included in the study due to withdrawal by parent. A total of 10 participants were assigned to treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) analysis set (PKS) included all participants with at least one PK sample in accordance with the PK sampling strategy.

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 (SAF) included all participants who received at least one dose of rivaroxaban.

6. Primary Endpoint

The registry lists the primary outcome as Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Day 1, measured over 30 minutes to 1.5 hours post-dose; 2 to 4 hours post-dose (bid dosing) and 30 minutes to 3 hours post-dose; 7 to 8 hours post-dose on Day 1 (tid dosing).

The primary endpoint is the concentration of rivaroxaban in plasma on Day 1, expressed in micrograms per liter (mcg/L). The record identifies the summary measure as a geometric mean and the variability measure as a geometric coefficient of variation. Sampling was scheduled at 30 minutes to 1.5 hours post-dose and 2 to 4 hours post-dose for BID dosing; for TID dosing, the windows were 30 minutes to 3 hours post-dose and 7 to 8 hours post-dose on Day 1.

Pharmacokinetic concentration measurements describe how much drug is present in the body at specified times after dosing. This can help characterize exposure in a population for whom the study is assessing pharmacokinetic and pharmacodynamic properties. General statistical context: concentration measurements are positive and can vary multiplicatively, so geometric summaries can be useful when values are right-skewed or when proportional variation is of interest. A geometric coefficient of variation describes relative dispersion on a multiplicative scale; it is not the same as an ordinary standard deviation.

The endpoint is not itself a clinical event such as bleeding or recurrent thrombosis. The registry record gives its definition and sampling windows but does not report the measured concentration values or their variability. Without those results, the observed exposure level and the precision of its summary cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies a geometric mean as the primary concentration summary and a geometric coefficient of variation as its dispersion measure. These choices concern how positive concentration data are summarized; they do not, by themselves, describe a treatment comparison or establish that a particular statistical model was used.

Why use a geometric mean?

General statistical context: a geometric mean summarizes positive values on a multiplicative scale. It is calculated conceptually by averaging logarithms and returning that average to the original scale. This can be suitable when values vary proportionally rather than by a constant additive amount, or when a distribution is right-skewed. A geometric mean is not interchangeable with an arithmetic mean. Without the individual observations or reported endpoint results, the reader cannot determine how much the choice of summary changes the interpretation in this study.

What does geometric coefficient of variation describe?

General statistical context: the coefficient of variation expresses dispersion relative to the scale of the measurements. In a geometric summary, this measure reflects multiplicative variation. It is not a confidence interval and does not directly indicate the precision of the estimated geometric mean. A confidence interval, when reported, describes uncertainty about an estimated quantity under the assumptions of the analysis. The registry record names a geometric coefficient of variation but does not report its value or a confidence interval for the primary outcome.

How should the sampling windows be read?

The endpoint was measured on Day 1 at post-dose windows specified separately for BID and TID dosing. The listed windows are 30 minutes to 1.5 hours post-dose and 2 to 4 hours post-dose for BID dosing, and 30 minutes to 3 hours post-dose and 7 to 8 hours post-dose for TID dosing. These are collection windows, not a report of the measured concentration at a single exact time. Interpretation depends on the actual sampling times and values, neither of which is reported in detail in the registry record. The record states that the pharmacokinetic analysis set included participants with at least one pharmacokinetic sample in accordance with the sampling strategy.

What does the design permit statistically?

The record identifies a single-group model, allocation as NA, and no masking. It separately lists adverse-event information for BID and TID suspension groups, but cautions that these are not a like-for-like control comparison. General statistical context: a controlled comparison aims to distinguish differences associated with treatment from differences that may arise from participant characteristics, timing, or other factors. A descriptive listing of groups does not provide that protection by itself. Because the registry record does not report assignment procedures or an adjusted comparison, no causal contrast between the dosing schedules should be inferred.

For event outcomes, counts describe the number of affected participants recorded within each group. They do not by themselves quantify uncertainty or establish comparative safety. General statistical context: confidence intervals around event rates can communicate uncertainty, while a suitable comparative analysis can address a defined contrast. Neither such intervals nor a comparative event analysis is reported in the record. The small listed counts also mean that the absence of a recorded event in a group should not be read as proof that the event cannot occur.

What do the planning illustrations represent?

The sample-size assumptions describe planning illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The illustrations use the stated fraction of the observed effect to define the effect to detect. For time-to-event outcomes, the assumptions describe a total number of events; for other outcomes, they describe participants per arm for 80% power or other stated power levels. These are planning scenarios, not observed power and not the enrollment rationale for this study. The record does not report the trial's own sample-size justification. Without the actual observed effect values or illustration results, the planning calculations cannot be evaluated as numeric estimates from the record.

The registry lists 0 analyses. This does not establish that no analyses were conducted; it means that no analyses are listed in this registry record. The record also does not specify a statistical model for the primary endpoint, a method for handling repeated or missing concentration measurements, or the treatment of multiple outcomes. Those methods are not reported in the registry record and should not be reconstructed from the endpoint summary alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures, including the primary Day 1 concentration measure and secondary measures concerning bleeding and thrombotic events. It lists 0 analyses. The record does not report a multiplicity strategy, such as a hierarchy of hypotheses, an adjustment to significance thresholds, or a plan to distinguish confirmatory outcomes from exploratory outcomes. Without such information, the individual outcomes should not be treated as though they necessarily represent separate confirmatory tests.

General statistical context: when many outcomes or comparisons are examined, the chance of at least one apparently notable finding can increase if each is interpreted without accounting for the set of analyses. A prespecified strategy can clarify which outcome is primary and how other findings should be interpreted. The registry record identifies a primary endpoint, but the full analysis plan and the handling of multiplicity are not reported in the registry record.

The primary pharmacokinetic analysis population is defined as the PK analysis set, including participants with at least one pharmacokinetic sample obtained in accordance with the sampling strategy. This definition gives a basic inclusion condition for that analysis population. It does not report how many participants met the condition, how many samples were missing, whether exclusions occurred, or how any incomplete data were handled. Those details are not reported in the registry record.

The listed enrollment is 10, but it should not be assumed that this is the size of the primary analysis set or the number contributing to every outcome. The record does not provide outcome-specific denominators beyond the adverse-event group counts. It also does not report an intention-to-treat population, a per-protocol population, an imputation method, or a sensitivity analysis for missing data. Accordingly, the available descriptions support only a limited account of the analysis populations and missing-data procedures.

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: atrial thrombosis (20.0%).

The adverse-event listings are separated by suspension schedule. Each group lists 5 participants at risk. In the Rivaroxaban Suspension Bid listing, serious events affected 0 participants and other events affected 1 participant; deaths are listed as 0. In the Rivaroxaban Suspension Tid listing, serious events affected 1 participant and other events affected 0 participants; deaths are listed as 0. These are descriptive counts from the registry record, not comparative estimates.

The record lists atrial thrombosis as a top serious-event term at 20.0%. The available details do not connect this term to a specific dosing listing or provide context for interpreting its percentage. It should not be combined with the group counts to infer an unreported denominator or event rate.

General statistical context: event counts in a small study can be useful for documenting what was recorded, but they give limited information about how often an event would occur in a wider population. A zero count does not establish absence of risk. The registry record does not report confidence intervals, an adjusted safety comparison, or enough detail to determine whether the events were considered related to treatment. It also does not provide the complete results for every listed bleeding or thrombotic outcome.

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

The record describes a completed early-phase study of oral rivaroxaban in children from birth to less than 6 months with arterial or venous thrombosis. Its primary endpoint is pharmacokinetic: plasma concentration on Day 1 at specified post-dose sampling windows. The endpoint is summarized in the record as a geometric mean with geometric coefficient of variation. This identifies what was intended to be measured, but the concentration results themselves are not reported in the registry record.

The reported safety entries document serious events, other events, and deaths for the BID and TID listings. They show that the registry recorded different event counts across those listings, but the study is not described as a randomized comparison and the record says the arms are not a like-for-like control comparison. Those counts therefore do not establish that one schedule caused more or fewer events than the other. The listed atrial thrombosis term also cannot be interpreted as a comparative estimate from the information recorded.

The record does not establish whether rivaroxaban is effective or ineffective for treating thrombosis in this population. A concentration endpoint is not a clinical efficacy outcome, and no primary concentration values or full clinical outcome results are available in the registry record. Nor do the safety counts establish that the treatment is safe or unsafe. They are observations from the registry record, with limited information about precision, attribution, and outcome-specific denominators.

General statistical context: evidence from a study is interpreted in light of its design, the measurements reported, and their uncertainty. A single-group descriptive record can characterize measurements and events that were collected, but it does not provide the same basis for causal conclusions as a randomized controlled comparison. The results support a narrow reading of the study design and listed safety counts; they do not support broader claims about comparative effects or population-level event frequencies.

13. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is about pharmacokinetic exposure in a very young population, rather than a direct comparison of clinical outcomes. Concentrations are measured at specified post-dose windows and summarized geometrically. Understanding the endpoint's scale and sampling schedule matters when interpreting what a concentration summary would mean. The registry record defines these features, although it does not report the numerical endpoint results.

The study also illustrates the limits of interpreting multiple regimen listings as if they were controlled arms. The record describes a single-group model, allocation as NA, and no masking. Its BID and TID adverse-event listings are explicitly not a like-for-like control comparison. In statistical terms, labels that divide results into groups do not alone establish random assignment or comparability. Avoiding causal language is therefore important when describing any differences between those listings.

The safety record is also a reminder that raw event counts and precision are separate issues. Counts describe what was recorded; they do not show how uncertain an event frequency may be in a broader population. The registry lists group-specific counts and a serious-event term, but does not report confidence intervals or a comparative safety analysis.

Finally, the record distinguishes the existence of a primary endpoint from the availability of its results. It specifies the endpoint and PK analysis-set definition, while the concentration values and variability are not reported. That gap constrains statistical interpretation more than familiarity with the endpoint label can resolve. The study is useful to examine as an example of how design, endpoint scale, analysis-population definitions, and incomplete result reporting jointly determine the strength and limits of conclusions.

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 statistical interpretation is that the registry record does not report the Day 1 concentration results, despite defining the geometric mean endpoint and its sampling windows. No numerical estimate of concentration or dispersion is available in the record, and no confidence interval is reported. The primary pharmacokinetic finding therefore cannot be judged for magnitude or precision.

The study is listed as single group, with allocation as NA and no masking. Although adverse events are presented separately for BID and TID suspension groups, the registry explicitly states that the arms are not a like-for-like control comparison. The record does not report how the dosing schedule was assigned, so a causal comparison between schedules is not supported by these listings.

The listed enrollment is 10, but the primary analysis-set definition requires at least one pharmacokinetic sample consistent with the sampling strategy. The record does not state how many participants met that criterion or provide outcome-specific denominators for the primary endpoint. Missing-data handling, exclusions, and sensitivity analyses are not reported in the registry record.

Further limitations include the absence of a reported statistical analysis plan, multiplicity approach, confidence intervals, and full results for the listed secondary outcomes. The serious-event term atrial thrombosis is reported at 20.0%, but the registry entries do not assign it to a specific dosing listing or provide enough context for a comparative interpretation. These gaps limit what can be inferred from the registry record; they should not be filled by assuming methods or results that are not reported.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Rivaroxaban for Treatment in Venous or Arterial Thrombosis in Neonates — NCT02564718.
• Registry record last updated 2018-07-10; status last verified 2018-06.
• Results first posted 2018-07-10.
• 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

NCT02564718 is a completed Phase 1 and Phase 2 study sponsored by Bayer. It enrolled children from birth to less than 6 months with arterial or venous thrombosis and studied weight-based oral rivaroxaban suspension prepared from granules. The record describes a 7-day study and lists a single-group model, allocation as NA, and no masking.

The primary endpoint is Day 1 plasma rivaroxaban concentration, summarized as a geometric mean with geometric coefficient of variation at post-dose windows specified for BID and TID dosing. The PK analysis set included participants with at least one sample collected in accordance with the sampling strategy. The registry lists 12 outcome measures and 0 analyses.

Safety listings report serious and other events and deaths for the BID and TID suspension groups. The record cautions that these groups are not a like-for-like control comparison. Primary concentration values, the full analysis plan, and further details needed for comparative interpretation are not reported in the registry record.