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 of LY2216684 and Warfarin in Healthy Subjects (NCT01263119), a na phase 1 study. The primary outcome is Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of S-Warfarin.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01263119 |
| Phase | Phase 1 |
| Condition | Major Depressive Disorder |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 18 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Eli Lilly and Company |
| Results posted | Yes |
2. Clinical Question
Population
The study title describes healthy subjects, and the registry lists enrollment 18. Its condition field lists Major Depressive Disorder, a label the registry record does not reconcile with the healthy-subject description. The primary analysis population included participants who received at least 1 dose of warfarin and had evaluable concentration data.
Intervention
The test exposure was 18-mg LY2216684 taken once daily on Days 1 to 12, with a single 10-mg warfarin oral dose coadministered on Day 3 of Period 2. The study also included an LY2216684-alone safety category.
Comparator
The reference exposure was a single 10-mg oral dose of warfarin on Day 1 of Period 1. The protocol description places a washout period of at least 14 days between the periods. This was not a randomized comparison; allocation is listed as NA, and masking as none.
Primary question
The primary question concerned whether S-warfarin exposure, measured by AUC0-∞, differed when warfarin was coadministered with LY2216684 rather than given alone. The endpoint description identifies the alone exposure as the reference and the coadministered exposure as the test. The numerical estimate and its confidence interval are not reported in the registry record, so the magnitude and precision of the result cannot be assessed.
3. Trial Design
This Phase 1 study, titled A Study of LY2216684 and Warfarin in Healthy Subjects, was registered as a single-group study with allocation listed as NA and masking listed as none. The registry records enrollment 18, status completed, a start date of 2010-12, and primary completion in 2011-02. The sponsor was Eli Lilly and Company.
The described dosing schedule has a warfarin-alone exposure in Period 1: a single 10-mg oral dose on Day 1. After a washout period of at least 14 days, Period 2 involved 18-mg LY2216684 orally once daily on Days 1 to 12, with a single 10-mg warfarin dose on Day 3. The endpoint description compares the warfarin-alone exposure with coadministration. This sequence allows the registry to describe both exposure conditions, but the record does not report a randomized allocation or masking procedure.
The safety results also classify participants under warfarin plus LY2216684, warfarin alone, and LY2216684 alone. The record does not explain how participants entered each safety category or how those categories relate to the described dosing sequence. It is therefore not appropriate to treat the listed categories as randomized, like-for-like groups. The registry explicitly notes that this is not a randomized comparison and that the arms are not a like-for-like control comparison.
The record's brief summary says the study was intended to examine how warfarin might affect LY2216684 and how LY2216684 might affect warfarin, while also collecting side-effect information. The listed primary endpoint addresses S-warfarin pharmacokinetics. Secondary outcomes include R-warfarin pharmacokinetics and warfarin pharmacodynamic measures. The protocol details and numerical results for those other measures 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.
Period 1
| Stage | Warfarin, LY2216684 + Warfarin |
|---|---|
| STARTED | 18 |
| COMPLETED | 16 |
| NOT COMPLETED | 2 |
Reasons for not completing this period:
| Reason | Warfarin, LY2216684 + Warfarin |
|---|---|
| Protocol Violation | 2 |
Period 2
| Stage | Warfarin, LY2216684 + Warfarin |
|---|---|
| STARTED | 16 |
| COMPLETED | 14 |
| NOT COMPLETED | 2 |
Reasons for not completing this period:
| Reason | Warfarin, LY2216684 + Warfarin |
|---|---|
| Adverse Event | 2 |
Analysis population for the primary outcome, as defined in the registry: The analysis population included participants who received at least 1 dose of warfarin and had evaluable concentration data.
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.
| Characteristic | Unit | Warfarin, LY2216684 + Warfarin |
|---|---|---|
| Participants analysed | 18 | |
| Age, Continuous | years | 38.2 (SD 6.6) |
| Sex: Female, Male: Female | Participants | 8 |
| Sex: Female, Male: Male | Participants | 10 |
| Race/Ethnicity, Customized: Black or African American | Participants | 6 |
| Race/Ethnicity, Customized: Multiple | Participants | 4 |
| Race/Ethnicity, Customized: White | Participants | 8 |
| Region of Enrollment: United States | Participants | 18 |
6. Primary Endpoint
The registry lists the primary outcome as Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of S-Warfarin, measured over Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | 90% Confidence Interval |
| Unit | nanogram*hour per milliliter (ng*hr/mL) |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the area under the plasma concentration-time curve from time 0 hour to infinity for S-warfarin, abbreviated AUC0-∞ and measured in nanogram*hour per milliliter (ng*hr/mL). AUC represents cumulative drug exposure over time: it incorporates both measured plasma concentrations and how long those concentrations persist. Extending the interval to infinity means the endpoint includes an estimate of exposure beyond the last observed concentration, although the registry record does not describe the estimation procedure.
S-warfarin is one of the forms of warfarin measured separately in the study. Measuring its concentration over time provides a pharmacokinetic way to assess whether coadministration with LY2216684 is associated with a change in warfarin exposure. The endpoint description identifies the warfarin-alone measurement as the reference and the coadministered measurement as the test. The listed analysis uses a least-squares geometric mean for each exposure condition.
AUC is useful for this question because a single concentration or a peak concentration alone would not describe total exposure across the sampling period. In general, a geometric mean summarizes positive measurements on a multiplicative scale and can be suitable when values are skewed. The registry record does not explain the choice of summary measure or report the numerical geometric means, their contrast, or the 90% confidence interval. Consequently, the endpoint definition is clear, but the posted record does not support an assessment of the observed size or precision of the pharmacokinetic difference.
Measurements were scheduled pre-dose and at 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours post-warfarin administration on Days 1 and 3. The record does not provide the observed concentration values or endpoint results associated with those times.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies a specific pharmacokinetic question: compare S-warfarin AUC0-∞ when warfarin was given alone with AUC0-∞ when warfarin was coadministered with LY2216684. It labels the warfarin-alone condition as the reference and coadministration as the test. However, no numerical estimate of either geometric mean, no contrast estimate, and no confidence interval result are reported in the registry record. Without those values, the observed direction, size, and precision of the primary result cannot be described.
The endpoint specifies a 90% confidence interval as its dispersion measure. In general, a confidence interval conveys uncertainty around an estimate: a narrower interval indicates greater precision, while a wider interval indicates less precision. It does not replace the estimate itself. Since the numerical interval is not reported, it is not possible to determine the range of values compatible with the posted estimate. The registry record also does not report a p-value for this endpoint.
The design description includes sequential exposure periods and a washout period, but the record does not report enough information to establish how period effects, sequence effects, or other potential influences were handled analytically. Nor does the record report an adjusted comparison method or a complete statistical analysis plan. The results should therefore not be interpreted as a causal estimate beyond what the record describes.
The registry reports other outcome domains, including R-warfarin pharmacokinetics and measures of warfarin pharmacodynamics. Those endpoints could add context to the S-warfarin exposure question, but their numerical results are not reported in the registry record. It is not possible to judge whether the patterns agree across outcomes or whether differences in pharmacokinetic exposure were accompanied by measured changes in INR.
The record lists safety counts for serious and other adverse events in three exposure categories. Those counts describe reported events and participants at risk within each category; they do not fill the gap in the primary pharmacokinetic result. Because the record says the groups are not a like-for-like control comparison, direct comparisons of their event counts should be cautious. The registry does not report enough detail to infer why the counts at risk differ between categories.
The record also includes planning assumptions for sample-size illustrations based on an observed effect. Such illustrations are not observed power, and they are not evidence that the study was designed to achieve a particular precision. Since the primary numerical effect is not reported in the registry record, the planning illustrations cannot be independently interpreted as evidence about the actual result. Overall, the registry documents the question, endpoint, and dosing conditions, but not the numerical outcome needed to estimate the size or certainty of the observed effect.
9. Statistical Methods Explained
The primary outcome is a continuous pharmacokinetic measure: AUC0-∞ of S-warfarin. The registry describes the summary as a least-squares geometric mean and specifies a 90% confidence interval. These labels identify the intended form of the summary, but the numerical analysis results and fuller model details are not reported in the registry record.
What does AUC measure?
In general, area under a concentration-time curve combines concentration and time into a measure of overall exposure. AUC0-∞ extends the exposure summary beyond the final sampling time to account for the remaining concentration-time curve. The record lists blood-sampling times through 240 hours after warfarin administration on Days 1 and 3, but does not describe the calculation used to estimate the tail of the curve, the handling of concentrations below assay limits, or the assay characteristics. Those details matter because endpoint values depend on both the observed concentrations and the method used to estimate exposure outside the observed window.
Why use a geometric mean?
In general, pharmacokinetic values are positive and may have a right-skewed distribution. A geometric mean summarizes values on a multiplicative scale, which can be useful when relative changes are of interest or when the distribution is skewed. A least-squares geometric mean typically reflects a model-based estimate rather than a simple raw average. The registry gives that label but does not report the model specification, transformations, covariates, assumptions, or estimation details. It is therefore not possible to reconstruct the analysis from the registry description alone.
What does the confidence interval add?
A confidence interval expresses uncertainty around an estimated quantity under the statistical method used. The endpoint lists a 90% confidence interval. In general, the interval should be considered alongside the estimate: an estimate describes the central result, and the interval indicates how precisely it was estimated. The interval is not a guarantee that the true value lies within its limits, and it does not itself establish whether a difference is important. The numerical interval and estimate are not reported in the registry record, so precision cannot be evaluated.
How should the exposure conditions be understood?
The endpoint description calls warfarin alone the reference and warfarin with LY2216684 the test. Those labels define the intended comparison; they do not by themselves establish randomization, masking, or a causal interpretation. Allocation is listed as NA, masking as none, and the study model as single group. The record explicitly warns that the listed arms are not a like-for-like control comparison. General concerns in sequential pharmacokinetic comparisons can include changes over time, period effects, and differences in which participants contribute evaluable data. Whether and how those issues were addressed is not reported in the registry record.
What do the planning assumptions mean?
The record describes sample-size calculations as planning illustrations computed from the observed effect, not as the trial's own design. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. In general, such calculations ask how many participants per arm would be needed under specified assumptions to detect a target effect at a chosen power. They are hypothetical planning quantities, not observed study outcomes and not observed power. The record states that time-to-event calculations report total events, while other calculations report participants per arm. That convention does not change the fact that the values are planning illustrations, not the number of participants actually analyzed.
The registry does not provide enough numerical endpoint information to evaluate the observed effect underlying those illustrations, and it does not report the trial's own sample-size justification. The assumptions therefore should not be treated as proof of adequate power or as a substitute for the estimate and confidence interval.
What analysis details remain unclear?
The primary analysis population is described as participants who received at least 1 dose of warfarin and had evaluable concentration data. The record does not report how many participants met that definition for the primary analysis, how missing or unevaluable concentrations were handled, whether any measurements were excluded, or whether sensitivity analyses were conducted. It also does not report the statistical model, degrees of freedom, diagnostics, or a multiplicity procedure. Those omissions limit reproducibility and prevent a full appraisal of the assumptions behind the stated summary.
10. Multiplicity, Missing Data and Analysis Populations
The registry counts 8 outcome measures and 8 analyses. The primary outcome is S-warfarin AUC0-∞. Listed secondary outcomes include R-warfarin AUC0-∞, R-warfarin maximum plasma concentration (Cmax), R-warfarin time to maximum concentration (Tmax), warfarin AUCINR, and maximum observed INR (INRmax). These measures address several pharmacokinetic and pharmacodynamic aspects of the study question.
When multiple outcomes are examined, the chance of at least one apparently unusual result can increase if each outcome is interpreted separately. In general, a prespecified multiplicity approach can address that issue, but the registry record does not report whether an adjustment was planned or used, nor does it describe a hierarchy among endpoints. It also does not provide numerical results for the listed secondary outcomes, so their consistency with the primary outcome cannot be assessed.
The primary analysis population is described as participants who received at least 1 dose of warfarin and had evaluable concentration data. The registry does not report the analysis population counts for the primary endpoint or the corresponding population definitions for each secondary endpoint. Missing-data handling, rules for evaluability, exclusions, imputation, and sensitivity analyses are not reported in the registry record. Thus, the extent to which missing or unevaluable data could affect the results cannot be assessed.
The record does not report a complete statistical analysis plan or clarify whether the endpoint definitions, analysis population, and methods were finalized before results were examined. This absence should be understood as missing documentation in the registry record, not proof that no such procedures existed.
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 |
|---|---|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | 0 | 16 | 0.0% |
| 10 mg Warfarin Alone (Reference) | 0 | 18 | 0.0% |
| 18 mg LY2216684 Alone | 0 | 16 | 0.0% |
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 |
|---|---|
| 10 mg Warfarin + 18 mg LY2216684 (Test) | 8 of 16 |
| 10 mg Warfarin Alone (Reference) | 6 of 18 |
| 18 mg LY2216684 Alone | 8 of 16 |
Most frequent non-serious adverse event terms
| Event term | Organ system | 10 mg Warfarin + 18 mg LY2216684 (Test) | 10 mg Warfarin Alone (Reference) | 18 mg LY2216684 Alone |
|---|---|---|---|---|
| Somnolence | Nervous system disorders | 1 of 16 | 0 of 18 | 4 of 16 |
| Nausea | Gastrointestinal disorders | 0 of 16 | 0 of 18 | 4 of 16 |
| Palpitations | Cardiac disorders | 3 of 16 | 0 of 18 | 0 of 16 |
| Constipation | Gastrointestinal disorders | 0 of 16 | 1 of 18 | 2 of 16 |
| Vomiting | Gastrointestinal disorders | 0 of 16 | 0 of 18 | 3 of 16 |
| Chills | General disorders | 0 of 16 | 0 of 18 | 3 of 16 |
| Dizziness | Nervous system disorders | 1 of 16 | 0 of 18 | 2 of 16 |
| Abdominal pain | Gastrointestinal disorders | 1 of 16 | 0 of 18 | 1 of 16 |
| Lip dry | Gastrointestinal disorders | 0 of 16 | 2 of 18 | 0 of 16 |
| Feeling jittery | General disorders | 1 of 16 | 0 of 18 | 1 of 16 |
The registry lists serious adverse events as 0 affected participants in each of the three categories: 10 mg Warfarin + 18 mg LY2216684 (Test), 10 mg Warfarin Alone (Reference), and 18 mg LY2216684 Alone. The numbers at risk for serious events are 16, 18, and 16, respectively. The record lists no serious-event terms. Death counts are null, which means the registry record does not provide a numerical death count; null should not be read as a reported zero.
For other adverse events, the registry lists 8 affected participants among 16 at risk in the test category, 6 among 18 at risk in the warfarin-alone reference category, and 8 among 16 at risk in the LY2216684-alone category. These are counts as recorded, not estimates adjusted for exposure duration or participant characteristics. The registry does not provide event-level detail in the registry record listed for this summary, and the categories are not described as randomized, like-for-like controls. Their counts should therefore be read descriptively rather than as evidence of a treatment-related difference. The record does not report the full definitions or collection procedures for these safety categories.
12. What the Result Does, and Does Not, Mean
This registry record establishes that the study addressed the pharmacokinetics and pharmacodynamics of warfarin when studied with LY2216684 in healthy subjects. It describes a warfarin-alone reference exposure and a coadministration test exposure, with S-warfarin AUC0-∞ named as the primary endpoint. It also identifies additional R-warfarin and INR outcomes, along with adverse-event summaries.
The record does not report numerical results for the primary endpoint. It therefore cannot establish from the posted information whether S-warfarin exposure was higher, lower, or similar under coadministration, nor how precisely any estimated difference was measured. A definition of an endpoint is not itself a result. The same limitation applies to the listed secondary pharmacokinetic and pharmacodynamic outcomes: their names are reported, but their numerical findings are not reported in the registry record.
The event counts describe what was recorded in the listed safety categories, but they do not establish comparative safety. The categories are not described as a randomized, like-for-like comparison, and the record does not provide the context needed to account for exposure duration, participant characteristics, or event-level patterns. Null death counts are not numerical zero counts.
More generally, a completed study status does not ensure that all results are available in the registry. The information recorded supports a description of the design and intended measurements, not a full assessment of the study's findings. It does not provide enough detail to determine whether the primary analysis was robust to missing data, whether multiplicity was addressed, or how any observed effect should be interpreted clinically. No treatment recommendation follows from the registry information.
13. Why This Trial Matters Statistically
This study illustrates how a drug-interaction question can be framed statistically through exposure conditions and a pharmacokinetic endpoint. S-warfarin AUC0-∞ captures cumulative exposure, while the comparison between warfarin alone and warfarin with LY2216684 defines the contrast of interest. The record also includes pharmacodynamic INR measures, which represent a distinct type of outcome from plasma drug concentrations.
It also illustrates why endpoint definitions and result reporting serve different purposes. The registry specifies the unit, summary measure, confidence-interval type, sampling schedule, and analysis-population definition for the primary endpoint. Those details help readers understand what was intended to be measured. Without the numerical estimate and interval, however, readers cannot evaluate the observed effect or its precision.
The design labels matter for interpretation. A single-group study with allocation listed as NA and masking listed as none should not be mistaken for a randomized comparison. The registry explicitly cautions that the arms are not like-for-like controls. That distinction is important when reading descriptive adverse-event counts and when considering whether the reported exposure conditions support a causal interpretation.
The record further shows the value of reporting analysis details alongside outcomes. The geometric-mean approach and 90% confidence interval are identified, while the underlying model, missing-data procedures, and multiplicity strategy are not reported. These details affect reproducibility and the strength of conclusions that can be drawn. The planning assumptions are also clearly distinguished from the trial's own design; such illustrations are not observed power. Together, these features make the study a useful example of why statistical interpretation depends on both design information and complete numerical results.
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 central limitation is that the registry record does not report numerical results for the primary endpoint. The geometric means, contrast estimate, and 90% confidence interval are absent, so the direction, magnitude, and precision of the S-warfarin exposure result cannot be assessed. Numerical results for the listed secondary outcomes are also not reported in the registry record.
The design information leaves important details unresolved. The registry describes sequential exposure periods and identifies reference and test conditions, but it does not report how period or sequence effects were considered. Allocation is listed as NA and masking as none; the record explicitly says this is not a randomized, like-for-like control comparison. The safety categories should not be interpreted as randomized groups.
The condition field lists Major Depressive Disorder, whereas the title and study description refer to healthy subjects. The registry record does not explain this discrepancy. It also does not explain how the three listed safety categories relate to the dosing schedule or why their numbers at risk differ.
For the primary analysis, the population is defined by warfarin exposure and evaluable concentration data, but the number meeting that definition is not reported. The record does not describe missing-data handling, exclusions, sensitivity analyses, the model specification, or multiplicity procedures. It also does not report assay or AUC extrapolation details. These limitations constrain reproducibility and leave uncertainty about how the posted endpoint would be affected by analysis choices.
Finally, the serious-event listings report zero affected participants, while death values are null rather than numerical counts. The record provides no basis to interpret null as zero. Other adverse-event counts are descriptive, and the design does not support treating them as direct comparative estimates.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of LY2216684 and Warfarin in Healthy Subjects — NCT01263119.
- Registry record last updated 2019-01-22; status last verified 2019-01.
- Results first posted 2018-10-19.
- 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
NCT01263119 is a completed Phase 1 study sponsored by Eli Lilly and Company, with recorded enrollment 18. The registry dates are start 2010-12 and primary completion 2011-02. The title and study description refer to healthy subjects, while the condition field lists Major Depressive Disorder; the record does not explain the difference.
The dosing description compares a single 10-mg warfarin dose alone in Period 1 with a 10-mg warfarin dose coadministered with 18-mg LY2216684 in Period 2, after a washout period of at least 14 days. The primary endpoint is S-warfarin AUC0-∞, summarized as a least-squares geometric mean with a 90% confidence interval. Numerical results for that endpoint are not reported in the registry record.
The record lists secondary pharmacokinetic and pharmacodynamic outcomes and adverse-event counts across three categories. It describes the study as nonrandomized and cautions that the categories are not like-for-like controls. Important analysis details, including numerical endpoint results, missing-data procedures, and multiplicity methods, are not reported in the registry record.