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 Evaluate the Pharmacokinetics and Safety of MK-4448 in Participants With Nonvalvular Atrial Fibrillation or Atrial Flutter (NCT01229254), a non-randomized phase 2 study. The primary outcome is Steady-state C12 hr on Days 14, 18, and 21 After Weight-based Dosing.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01229254 |
| Phase | Phase 2 |
| Condition | Atrial Fibrillation, Atrial Flutter |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 189 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Portola Pharmaceuticals |
| Results posted | Yes |
2. Clinical Question
Population
Adults with nonvalvular atrial fibrillation or atrial flutter. The registry record describes the primary analysis population as a per-protocol set: allocated patients who received at least one dose, met the stated treatment-compliance requirements, took treatment within 24 hours before steady-state sampling, and had at least two post-steady-state blood samples collected.
Intervention
Betrixaban dosing was organized around participant weight and baseline amiodarone use. The listed groups were betrixaban 60 mg for lower-weight participants, betrixaban 90 mg for higher-weight participants, and betrixaban 30 mg with concomitant baseline amiodarone.
Comparator
This was a non-randomized study, not a like-for-like control comparison. The groups were defined by weight or concomitant amiodarone use, so differences between them cannot be interpreted as if they arose from random assignment to interchangeable treatments.
Primary question
What steady-state betrixaban concentration was measured 12 hours after dosing on Days 14, 18, and 21 in the weight-based groups? This is a pharmacokinetic question about drug exposure, rather than a question about whether betrixaban prevents clinical events or improves symptoms.
The registry describes the study’s purpose as optimizing drug exposure in the target population. It also lists a secondary pharmacokinetic outcome for the same sampling time points after dosing based on weight and amiodarone use. The registry record does not report the numerical primary endpoint estimates, so the magnitude and precision of the observed concentrations cannot be assessed from the posted results.
3. Trial Design
This was a phase II, open-label, non-randomized, parallel-group study of betrixaban in adults with nonvalvular atrial fibrillation or atrial flutter. The registry lists Portola Pharmaceuticals as the sponsor. The study started in 2010-09, had primary completion in 2010-12, and is recorded as completed. Enrollment is listed as 189.
The listed interventions were betrixaban 30 mg, betrixaban 60 mg, betrixaban 90 mg, and amiodarone. The arm descriptions distinguish betrixaban 60 mg for participants with lower weights, betrixaban 90 mg for participants with higher weights, and betrixaban 30 mg for participants taking baseline amiodarone. The posted group labels identify the 60 mg group as below 80 kg and the 90 mg group as 80 kg or more. The amiodarone group is described as betrixaban 30 mg with concomitant baseline amiodarone.
Because assignment was not randomized and the groups reflect weight or amiodarone use, the design does not establish an exchangeable control group for comparing treatment effects. The open-label status means masking is listed as none. The primary endpoint concerns steady-state betrixaban concentration 12 hours after dosing on Days 14, 18, and 21 of the pharmacokinetic period. The analysis population is described as per protocol, with treatment exposure, compliance, timing, and blood-sampling requirements. The registry record does not report a sample-size justification or additional details of the statistical plan.
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: Patients weighing \< 80 kg received daily betrixaban 60 mg, patients weighing ≥ 80 kg received daily betrixaban 90 mg, and patients on amiodarone at screening, regardless of weight, received daily betrixaban 30 mg. 241 patients were screened for study participation. Of these patients, 189 were enrolled and received at least 1 dose of study drug.
Overall Study
| Stage | Betrixaban 30 mg (+Amiodarone) | Betrixaban 60 mg (<80 kg) | Betrixaban 90 mg (≥80 kg) |
|---|---|---|---|
| STARTED | 42 | 74 | 73 |
| COMPLETED | 27 | 58 | 61 |
| NOT COMPLETED | 15 | 16 | 12 |
Reasons for not completing this period:
| Reason | Betrixaban 30 mg (+Amiodarone) | Betrixaban 60 mg (<80 kg) | Betrixaban 90 mg (≥80 kg) |
|---|---|---|---|
| Not Continuing Into Safety Extension | 3 | 1 | 1 |
| Adverse Event | 4 | 5 | 3 |
| Lost to Follow-up | 3 | 0 | 1 |
| Physician Decision | 0 | 3 | 0 |
| Protocol Violation | 4 | 6 | 5 |
| Withdrawal by Subject | 1 | 0 | 1 |
| Non-compliance with Study Drug | 0 | 1 | 1 |
Analysis population for the primary outcome, as defined in the registry: Per protocol analysis set, which includes all allocated patients who received at least one dose of study treatment and who were ≥ 90% compliant with study treatment, took study treatment within 24 hours prior to steadystate blood sampling, had at least two post steady-state blood samples collected, and not on amiodarone.
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: All enrolled patients who took at least 1 dose of study medication
| Characteristic | Unit | Betrixaban 30 mg (+Amiodarone) | Betrixaban 60 mg (<80 kg) | Betrixaban 90 mg (≥80 kg) | Total |
|---|---|---|---|---|---|
| Participants analysed | 42 | 74 | 73 | 189 | |
| Age, Continuous | years | 72.4 (SD 9.87) | 77.1 (SD 7.12) | 71.2 (SD 9.21) | 73.8 (SD 8.98) |
| Age, Customized: <75 years | Participants | 23 | 24 | 46 | 93 |
| Age, Customized: >=75 years | Participants | 19 | 50 | 27 | 96 |
| Sex: Female, Male: Female | Participants | 19 | 46 | 16 | 81 |
| Sex: Female, Male: Male | Participants | 23 | 28 | 57 | 108 |
6. Primary Endpoint
The registry lists the primary outcome as Steady-state C12 hr on Days 14, 18, and 21 After Weight-based Dosing, measured over Days 14, 18, and 21 of the PK period.
| Element | Registry entry |
|---|---|
| Result type | Geometric Least Squares Mean |
| Measure of spread | 90% Confidence Interval |
| Unit | ng/mL |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the steady-state betrixaban concentration measured 12 hours after dosing on Days 14, 18, and 21 of the pharmacokinetic period. Its unit is ng/mL. The stated population is the per-protocol analysis set, and the endpoint is described for the low- and high-weight groups after weight-based dosing.
A concentration measured at a specified time after a dose is a pharmacokinetic measure: it describes drug exposure at that sampling point. The registry reports the endpoint as a geometric least squares mean with a 90% confidence interval. In general, a geometric mean is useful for measurements that are positive and may be distributed unevenly, because it summarizes values on a multiplicative rather than purely additive scale. A least squares mean is an estimate from a statistical model; the model details used for this endpoint are not reported in the registry record.
In general, a confidence interval communicates uncertainty around an estimated quantity. Its width reflects how precisely the quantity has been estimated under the analysis. The registry record does not report the primary endpoint’s numerical estimate or interval, so neither the concentration level nor its precision can be described. This endpoint measures exposure, not clinical benefit, and it does not by itself establish safety or efficacy.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The study addresses pharmacokinetic exposure, with the stated aim of optimizing exposure in the target population. Its primary outcome is a concentration at a defined time after dosing, summarized as a geometric least squares mean and 90% confidence interval. The numerical estimates for that endpoint are not reported in the registry record. Consequently, the posted results do not support a description of the observed concentration level, its uncertainty, or the size of any difference between weight-based groups.
The design limits what can be inferred from between-group contrasts. Participants were not randomized, and the groups were organized by weight or baseline amiodarone use. Such groups may differ in characteristics connected to the reason for the dosing scheme. A contrast between them would therefore not isolate a causal effect of dose or amiodarone use in the way a randomized comparison could. The registry explicitly cautions that the arms are not a like-for-like control comparison.
The adverse-event listings provide descriptive counts for each recorded group. Serious adverse events affected 6 of 42 in the betrixaban 30 mg with amiodarone group, 13 of 74 in the betrixaban 60 mg group, and 6 of 73 in the betrixaban 90 mg group. Other adverse events affected 18 of 42, 34 of 74, and 35 of 73, respectively. These counts do not establish that betrixaban caused the events, and they should not be treated as randomized comparative estimates. The registry does not report deaths in these group entries.
The registry records two outcome measures and one analysis. It does not report the statistical model details, multiplicity procedures, missing-data methods, or a numerical primary endpoint result. Those omissions limit assessment of how the pharmacokinetic estimates were derived and how uncertainty across the listed outcomes or time points was handled. The study’s completed status does not fill those reporting gaps. Its results, as recorded, are best read as a non-randomized exposure and safety record rather than as evidence from a controlled test of clinical outcomes.
Any sample-size illustrations associated with the posted results are planning calculations based on an observed effect, not observed power and not the study’s original design justification. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They do not remedy the lack of random assignment or supply the missing primary endpoint estimates.
9. Statistical Methods Explained
The registry identifies the primary endpoint as a geometric least squares mean with a 90% confidence interval. It does not report the model specification, covariates, or detailed estimation procedure. The concepts below explain how to read the stated measures in general; they do not imply that a particular unreported method was used.
What does a geometric least squares mean represent?
A geometric mean summarizes positive measurements on a multiplicative scale. It is often helpful when values are skewed, so that a few comparatively large measurements do not dominate a summary as they might on an arithmetic scale. In general, the geometric mean is obtained by taking the mean after a logarithmic transformation and then converting the result back to the original scale. The registry’s use of the label geometric least squares mean indicates a model-based estimate, but the model and any adjustment factors are not reported.
A least squares mean is also called a marginal mean in some settings. In general, it estimates a group mean from a fitted statistical model, often with specified covariates or averaging over model terms. Without the model specification, readers cannot determine which covariates were included, whether the estimate was adjusted, or how the data from the scheduled days contributed to it. These details are not reported in the registry record.
How should the confidence interval be read?
A confidence interval expresses uncertainty around an estimate under the statistical method used. A narrower interval indicates greater precision than a wider interval, while the interval’s endpoints describe a range of values compatible with the analysis. The primary endpoint is reported with a 90% confidence interval. That interval is not a probability statement that the true value lies inside the particular interval, and it is not itself a test of whether a treatment works. The endpoint’s estimate and interval are not reported in the registry record, so their width and location cannot be interpreted.
The concentration is measured 12 hours after dosing. This is a pharmacokinetic sampling point, not a direct measure of clinical events. The scheduled sampling days are Days 14, 18, and 21. Repeated measurements can describe exposure over time, but the registry record does not specify whether the primary estimate pools those measurements, estimates them separately, or uses another model structure. It would be inappropriate to infer that analysis detail from the endpoint label alone.
Why does the non-randomized design matter?
Random assignment is used in general to help balance both measured and unmeasured characteristics across groups. Here, allocation is listed as non-randomized, and the group descriptions are tied to participant weight or baseline amiodarone use. A difference between groups could reflect those characteristics, other group differences, or the dosing regimen. Without randomization, statistical adjustment can address only measured factors included in an appropriate model; the registry does not report whether such adjustment was performed. Even a model-adjusted contrast would require careful interpretation.
Open-label means masking is listed as none. A laboratory concentration is more objective than a self-reported outcome, but open-label status can still matter for treatment management, reporting, or other aspects of study conduct. The record does not describe how those possibilities were handled. The design is therefore useful to describe the exposure strategy studied, but it should not be read as a randomized comparative efficacy experiment.
What do the sample-size illustrations mean?
In general, a planning calculation estimates the number of participants needed under specified assumptions to detect an effect at a chosen significance level and power. The stated planning illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect expressed as a fraction of the observed effect. These are planning assumptions, not evidence that the trial was designed with those assumptions. A calculated sample size is not observed power, and it does not establish that an analysis is unbiased or clinically important. The original sample-size justification is not reported in the registry record.
The illustrations describe participants per arm for a stated power level when applicable; time-to-event calculations, in general, instead concern total events. Such calculations are only as informative as their assumptions and the effect estimate used. No additional sample-size values or assumptions should be inferred beyond those reported for the posted planning exercise.
What do the safety counts describe?
The adverse-event record gives group counts for participants at risk and participants affected by serious and other adverse events. These are descriptive summaries. In general, counts and denominators give context for how often an event was recorded in each group, but unadjusted counts alone do not show causation. The weight-based and amiodarone groups are not randomized comparison groups, so differences in counts should not be interpreted as estimates of treatment effects. The registry does not report enough detail to assess event timing, exposure duration, or event-level adjudication.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists two outcome measures and one analysis. The primary measure concerns steady-state concentration after weight-based dosing; the secondary measure concerns steady-state concentration after weight- and amiodarone-based dosing. The primary outcome includes sampling on Days 14, 18, and 21. The record does not explain whether those time points were analyzed jointly or separately, or how inference across outcome measures and time points was controlled.
Multiplicity arises in general when several outcomes, time points, groups, or statistical tests are examined. Testing multiple hypotheses can increase the chance of a nominally notable finding by chance if no adjustment or prespecified hierarchy is used. Whether a correction was applied, or whether an analysis hierarchy was specified, is not reported in the registry record. The listed analysis count alone does not establish how many estimates or tests were made.
The primary analysis population is described as per protocol. It includes allocated patients who received at least one dose, were at least 90% compliant with study treatment, took treatment within 24 hours before steady-state blood sampling, and had at least two post-steady-state samples collected. These criteria define which participants contributed to the stated analysis; the registry does not report a complementary intention-to-treat analysis.
Missing-data methods, the amount or pattern of missing outcome data, and any sensitivity analyses are not reported in the registry record. Requiring blood samples for inclusion can affect who contributes to a per-protocol estimate if some participants lack the required measurements. The record does not describe how that possibility was assessed or addressed. As a result, readers cannot evaluate whether missing measurements may have influenced the reported pharmacokinetic findings.
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 |
|---|---|---|---|
| Betrixaban 30 mg (+Amiodarone) | 6 | 42 | 14.3% |
| Betrixaban 60 mg (<80 kg) | 13 | 74 | 17.6% |
| Betrixaban 90 mg (≥80 kg) | 6 | 73 | 8.2% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Betrixaban 30 mg (+Amiodarone) | 18 of 42 |
| Betrixaban 60 mg (<80 kg) | 34 of 74 |
| Betrixaban 90 mg (≥80 kg) | 35 of 73 |
Most frequent serious adverse event terms
| Event term | Organ system | Betrixaban 30 mg (+Amiodarone) | Betrixaban 60 mg (<80 kg) | Betrixaban 90 mg (≥80 kg) |
|---|---|---|---|---|
| Basal cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 42 | 2 of 74 | 2 of 73 |
| Chest pain | General disorders | 1 of 42 | 2 of 74 | 0 of 73 |
| Atrial fibrillation | Cardiac disorders | 1 of 42 | 1 of 74 | 0 of 73 |
| Sepsis | Infections and infestations | 1 of 42 | 1 of 74 | 0 of 73 |
| Squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1 of 42 | 1 of 74 | 0 of 73 |
| Anaemia | Blood and lymphatic system disorders | 1 of 42 | 0 of 74 | 0 of 73 |
| Thrombocytopenia | Blood and lymphatic system disorders | 1 of 42 | 0 of 74 | 0 of 73 |
| Cardiac failure congestive | Cardiac disorders | 0 of 42 | 1 of 74 | 0 of 73 |
| Coronary artery stenosis | Cardiac disorders | 0 of 42 | 1 of 74 | 0 of 73 |
| Vertigo | Ear and labyrinth disorders | 0 of 42 | 1 of 74 | 0 of 73 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Betrixaban 30 mg (+Amiodarone) | Betrixaban 60 mg (<80 kg) | Betrixaban 90 mg (≥80 kg) |
|---|---|---|---|---|
| Dizziness | Nervous system disorders | 0 of 42 | 9 of 74 | 5 of 73 |
| Fatigue | General disorders | 3 of 42 | 5 of 74 | 5 of 73 |
| Contusion | Injury, poisoning and procedural complications | 4 of 42 | 7 of 74 | 2 of 73 |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | 2 of 42 | 3 of 74 | 6 of 73 |
| Diarrhoea | Gastrointestinal disorders | 2 of 42 | 4 of 74 | 5 of 73 |
| Oedema peripheral | General disorders | 3 of 42 | 3 of 74 | 5 of 73 |
| Urinary tract infection | Infections and infestations | 2 of 42 | 9 of 74 | 0 of 73 |
| Upper respiratory tract infection | Infections and infestations | 3 of 42 | 1 of 74 | 6 of 73 |
| Nausea | Gastrointestinal disorders | 3 of 42 | 2 of 74 | 5 of 73 |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 2 of 42 | 2 of 74 | 4 of 73 |
Serious events with the highest arm-level rate: basal cell carcinoma (2.7%), chest pain (2.7%), anaemia (2.4%), thrombocytopenia (2.4%), atrial fibrillation (2.4%).
The registry reports serious adverse events using a group denominator and an affected count. Serious adverse events affected 6 of 42 in the betrixaban 30 mg with amiodarone group, 13 of 74 in the betrixaban 60 mg group, and 6 of 73 in the betrixaban 90 mg group. Other adverse events affected 18 of 42, 34 of 74, and 35 of 73, respectively. These are the recorded group counts; they do not show whether an event was caused by study treatment.
The registry’s listed serious-event terms and percentages are basal cell carcinoma, 2.7%; chest pain, 2.7%; anaemia, 2.4%; thrombocytopenia, 2.4%; atrial fibrillation, 2.4%; and gastrointestinal haemorrhage, 2.4%. The record does not specify the denominator for these term percentages in the listed summary, so they should not be assigned to a particular group from this information alone. Deaths are not reported in the registry record.
Because allocation was non-randomized and the groups were defined by weight or amiodarone use, comparisons of the event counts are descriptive rather than like-for-like treatment contrasts. The counts also do not supply details about timing, duration, or event severity beyond the serious and other categories recorded.
12. What the Result Does, and Does Not, Mean
The study asks a focused pharmacokinetic question: what betrixaban concentration is present 12 hours after dosing at scheduled steady-state sampling points in groups defined by weight-based dosing and amiodarone use? That question is relevant to characterizing drug exposure in the population described by the registry. The recorded aim was to optimize exposure in that target population.
The primary endpoint is not a clinical outcome such as prevention of an event or improvement in symptoms. A concentration estimate can describe exposure, but it cannot by itself establish clinical benefit, safety, or an appropriate dose for an individual. The numerical primary endpoint estimate and its confidence interval are not reported in the registry record, so no conclusion about the observed concentration or its precision can be drawn from the posted results.
The safety listings report affected counts in the betrixaban groups, but descriptive counts do not establish causation. The record does not describe a randomized control group. Since participants were allocated without randomization and group definitions reflect weight or concomitant amiodarone, group differences could not be interpreted as clean causal contrasts. The study also does not provide a basis for claiming that one group had better clinical outcomes than another.
Accordingly, the record supports understanding the study’s design, intended pharmacokinetic measure, per-protocol criteria, and recorded adverse-event summaries. It does not support a conclusion about treatment efficacy, comparative safety, or a clinically meaningful exposure target. Those judgments would require reported outcome estimates and further design and analysis details that are not reported in the registry record.
13. Why This Trial Matters Statistically
This study illustrates the distinction between measuring drug exposure and testing clinical outcomes. The primary outcome is a concentration at a specified time after dosing, summarized as a geometric least squares mean. That makes the analysis a pharmacokinetic investigation, consistent with the stated purpose of optimizing exposure, rather than a randomized trial of clinical benefit.
It also highlights why group structure matters when interpreting estimates. The groups are organized around weight-based dosing and baseline amiodarone use, and allocation is non-randomized. A difference across these groups cannot automatically be attributed to dose or concomitant medication, because the group-defining characteristics are not balanced by random assignment. Descriptive summaries can still characterize what was recorded in each group, but their interpretation should remain tied to the design.
The registry’s per-protocol definition is another useful statistical feature to notice. The analysis requires treatment exposure, a stated level of compliance, appropriate timing before sampling, and a minimum number of post-steady-state samples. Such criteria specify the population whose measurements contribute to the primary analysis, while also making missing samples and exclusions relevant to interpretation. The missing-data handling and statistical model details are not reported.
Finally, the record shows the value of distinguishing numerical results from study objectives and design descriptions. Although the endpoint and analysis population are named, the primary estimate and its confidence interval are not reported. Without them, the precision and level of observed exposure cannot be evaluated. The study remains informative as a record of the question and design, but its posted information does not support conclusions beyond that scope.
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 most direct limitation for interpreting the primary outcome is that its numerical estimate and 90% confidence interval are not reported in the registry record. Without those values, the observed concentration and its precision cannot be assessed. The record identifies a model-based summary but does not describe the model, covariates, or how measurements from the scheduled sampling days were incorporated.
Allocation was non-randomized, masking was none, and group definitions reflect weight or baseline amiodarone use. These features limit causal comparison between groups. The registry itself cautions that the arms are not a like-for-like control comparison. The recorded enrollment is 189, but the per-protocol population has additional treatment, compliance, timing, and sampling requirements; the number contributing to each endpoint is not reported.
Details needed to assess robustness are also not reported in the registry record. These include the statistical plan, sample-size justification, multiplicity handling, missing-data methods, and sensitivity analyses. The listed adverse-event summaries do not report deaths, and further details on event timing or exposure duration are not reported. These limitations constrain interpretation of the record; they do not establish that an unreported analysis or procedure was absent from the study itself.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Evaluate the Pharmacokinetics and Safety of MK-4448 in Participants With Nonvalvular Atrial Fibrillation or Atrial Flutter — NCT01229254.
- Registry record last updated 2023-08-07; status last verified 2023-08.
- Results first posted 2017-09-18.
- 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
NCT01229254 is a completed phase II, open-label, non-randomized, parallel-group study of betrixaban in adults with nonvalvular atrial fibrillation or atrial flutter. Portola Pharmaceuticals is listed as the sponsor. The registry records enrollment of 189, a start in 2010-09, and primary completion in 2010-12.
The primary endpoint is steady-state betrixaban concentration 12 hours after dosing on Days 14, 18, and 21, reported as a geometric least squares mean with a 90% confidence interval. The analysis population is per protocol. The record lists two outcome measures and one analysis, but does not report the numerical primary endpoint estimates or detailed statistical methods.
Serious and other adverse-event counts are recorded for the three betrixaban groups. Since allocation was non-randomized and groups reflect weight or amiodarone use, those counts are descriptive rather than a randomized comparison. The registry describes the study purpose as optimizing exposure in the target population.