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 Effects of Denosumab on the Pharmacokinetics of Etanercept (NCT01294397), a na phase 1 study. The primary outcome is Area Under the Serum Concentration-time Curve From 0 to 168 Hours (AUC0-168) for Etanercept.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01294397 |
| Phase | Phase 1 |
| Condition | Postmenopausal, Osteopenia, Rheumatoid Arthritis |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 19 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Amgen |
| Results posted | Yes |
2. Clinical Question
Population
Postmenopausal women with low bone mineral density and rheumatoid arthritis. The registry record lists 19 enrolled participants and identifies osteopenia and osteoporosis among the conditions.
Intervention
Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. On study day 8, they received a single 60 mg subcutaneous injection of denosumab.
Comparator
There was no separate randomized control group. The primary endpoint description compares etanercept administered alone on day 1 with etanercept administered after denosumab, assessed on day 22.
Primary question
How did etanercept’s area under the serum concentration-time curve from 0 to 168 hours differ between the day 1 assessment and the day 22 assessment after denosumab? The registry record does not report the numerical endpoint results.
The study focused on pharmacokinetics: how etanercept concentrations in serum change over time. Its stated primary objective was to characterize the effect of a single denosumab dose on etanercept pharmacokinetics, using area under the concentration-time curve and maximum observed serum concentration. The primary registered outcome was the area under the curve from 0 to 168 hours.
This is a question about drug exposure, not a direct test of rheumatoid arthritis symptoms, bone outcomes, or clinical benefit. Secondary outcomes listed in the record include time to maximum etanercept concentration, serum denosumab concentration, and percent change from baseline in serum C-telopeptide. Numerical results for these outcomes are not reported in the registry record.
3. Trial Design
The registry identifies this as a Phase 1, single-group study with an enrollment of 19. Allocation is listed as not applicable, and masking is listed as none. These features mean the record does not describe a randomized comparison between separately assigned treatment groups. Instead, the primary endpoint description uses measurements from participants receiving etanercept alone and later receiving etanercept after denosumab.
Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks. A single 60 mg subcutaneous denosumab injection was administered on study day 8. The primary outcome description specifies an etanercept assessment on day 1 and another on day 22, which was 14 days after denosumab dosing. The record describes day 22 as close to the time of maximum observed denosumab serum concentration and approximately one week after maximal pharmacodynamic effects were attained.
For each AUC assessment, samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose. The outcome population is described as participants with available AUC data. The number with available data for this endpoint is not reported in the registry record, so the enrolled total should not be assumed to equal the number analyzed.
The study status is terminated. The reason for termination, whether the planned enrollment was completed, and the details of any changes to conduct are not reported in the registry record. Start and primary completion are listed as 2011-03 and 2016-01, respectively. These dates do not establish why the study ended or whether the planned assessments were completed as intended.
Because measurements were obtained at different times in one treatment group, the design does not provide a concurrent control group. Any interpretation of the day 1 and day 22 contrast must account for that design and the absence of a randomized, like-for-like comparison.
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: Following determination of eligibility at screening, 19 participants were enrolled into a 4-week run-in period of etanercept 50 mg subcutaneous once-weekly injection to ensure steady-state.
Overall Study
| Stage | Etanercept + Denosumab |
|---|---|
| STARTED | 19 |
| COMPLETED | 17 |
| NOT COMPLETED | 2 |
Reasons for not completing this period:
| Reason | Etanercept + Denosumab |
|---|---|
| Withdrawal by Subject | 1 |
| Administrative Decision | 1 |
Analysis population for the primary outcome, as defined in the registry: Participants with available AUC 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 | Etanercept + Denosumab |
|---|---|---|
| Participants analysed | 19 | |
| Age, Continuous | years | 63.1 (SD 6.6) |
| Sex: Female, Male: Female | Participants | 19 |
| Sex: Female, Male: Male | Participants | 0 |
| Race/Ethnicity, Customized: Hispanic/Latino | participants | 1 |
| Race/Ethnicity, Customized: Not Hispanic/Latino | participants | 18 |
| Race/Ethnicity, Customized: American Indian or Alaska Native | participants | 0 |
| Race/Ethnicity, Customized: Asian | participants | 0 |
| Race/Ethnicity, Customized: Black (or African American) | participants | 1 |
| Race/Ethnicity, Customized: Mixed race | participants | 0 |
| Race/Ethnicity, Customized: Native Hawaiian or Other Pacific Islander | participants | 0 |
| Race/Ethnicity, Customized: White | participants | 18 |
6. Primary Endpoint
The registry lists the primary outcome as Area Under the Serum Concentration-time Curve From 0 to 168 Hours (AUC0-168) for Etanercept, measured over Day 1 and day 22; at each time point samples were taken predose and 2, 3, 4, 5, 6 and 8 days postdose..
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | day*μg/mL |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is the area under the etanercept serum concentration-time curve from 0 to 168 hours, expressed in day*μg/mL. An area under the curve summarizes concentration across a defined period rather than describing just one blood sample. A larger or smaller value would indicate a difference in measured exposure over that sampling interval, but the registry record does not report the observed values or the direction of any difference.
The endpoint was assessed for etanercept administered alone on day 1 and after denosumab administration on day 22. Samples were collected predose and 2, 3, 4, 5, 6 and 8 days postdose. The endpoint description characterizes the later assessment as occurring 14 days after denosumab dosing, near the time of maximum observed denosumab serum concentration and about one week after maximal pharmacodynamic effects were attained.
In general, pharmacokinetic measures such as AUC are used to characterize drug exposure over time. This can help address whether exposure differs under the conditions being compared. AUC does not, by itself, establish a clinical effect or explain why a measured difference occurred. The registry record also identifies maximum observed serum concentration as part of the study’s stated objective, but its numerical result is not reported. The primary outcome is listed as a mean with standard deviation; the actual mean and dispersion are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record gives the study question, treatment schedule, endpoint definition, and enrollment, but does not report the numerical primary endpoint results. In particular, it does not report the day 1 or day 22 AUC means, their standard deviations, or a numerical contrast between assessments. Therefore, the magnitude, direction, and precision of the observed pharmacokinetic difference cannot be characterized from the registry record.
The study’s stated aim was to characterize the effect of denosumab on etanercept pharmacokinetics. That aim should not be mistaken for a reported finding. Without numerical AUC results, it is not possible to say whether the measurements were similar or different, or how uncertain any contrast was. Numerical results for maximum observed concentration and the listed secondary outcomes are also not reported in the registry record.
The design is important to interpretation. This was a single-group study, not a randomized comparison with a concurrent control. The primary endpoint description contrasts etanercept administered alone at one assessment with etanercept assessed after denosumab at a later time. Such a comparison can describe the measurements collected under those conditions, but the design does not isolate a treatment effect as securely as a randomized concurrent comparison would. Time, study conduct, and other changes between assessments cannot be separated from denosumab exposure on the basis of the design information in the registry record.
The outcome population is participants with available AUC data, while 19 participants were enrolled. The analyzed number for the primary endpoint is not reported in the registry record. Without that number and information about missing assessments, the reader cannot determine how complete the endpoint data were or whether the analysis included every enrolled participant.
The study is listed as terminated, but the reason is not reported in the registry record. Termination alone does not establish that the results were unfavorable, that a safety concern occurred, or that the primary endpoint was not measured. Those conclusions would require information not present in the registry record.
Overall, the posted record supports a description of the clinical question and design, but not a conclusion about the observed AUC effect. Interpretation should remain limited to the registered plan and the safety counts reported, without treating absent efficacy or pharmacokinetic results as evidence of no effect.
9. Statistical Methods Explained
The registry lists the primary endpoint as a mean continuous measure with standard deviation. A mean describes the central value of a set of measurements, while the standard deviation describes how dispersed individual measurements are around that mean. Reporting both can help readers understand not only the average exposure but also the variability among participants. Neither the mean nor the standard deviation for the primary endpoint is reported in the registry record.
What does the AUC measure?
In general, an area under the concentration-time curve combines concentration measurements across a specified time interval into a summary of exposure. Here, the registered interval is 0 to 168 hours, and the unit is day*μg/mL. The sampling schedule is specified as predose and 2, 3, 4, 5, 6 and 8 days postdose. AUC can be useful when a single concentration measurement would not represent the full concentration profile. It remains a pharmacokinetic measure: it does not directly measure symptoms, function, or another clinical outcome.
How should a confidence interval be understood?
In general, a confidence interval describes uncertainty around an estimated quantity. A narrow interval indicates greater precision than a wide interval, given the analysis and assumptions used. It does not show the range of individual participant responses, and it is not a guarantee that the true value lies within that particular interval. The registry record does not report a confidence interval for the primary endpoint or its contrast, so precision cannot be assessed from the record.
Why does the design affect the analysis?
The record describes a single group and measurements at day 1 and day 22. That is not the same as assigning participants randomly to separate denosumab and no-denosumab groups. In general, repeated measurements from the same participants can be compared using methods that account for their within-participant relationship. Whether such a paired analysis was used, and what statistical model or test was applied, are not reported in the registry record. It would be inappropriate to assume a particular method from the schedule alone.
A concurrent control group can help distinguish changes associated with treatment from changes that occur over time or through other influences. This study’s listed design does not include such a randomized control group. The day 1 and day 22 comparison is therefore informative about the observed assessments but cannot, by design alone, eliminate alternative explanations for a difference between them.
What does the sample-size illustration mean?
In general, a sample-size calculation describes how many participants may be needed under specified assumptions to detect a defined effect with a chosen probability. The registry record does not report the study’s sample-size justification or a planned power calculation. Any planning illustration based on an observed effect is a retrospective, assumption-dependent scenario, not the study’s original design rationale and not observed power. It should not be interpreted as evidence that the study was adequately powered or that a result was statistically persuasive.
The record’s general assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Those assumptions do not match the listed single-group study structure as a randomized two-arm comparison. In general, sample-size illustrations depend strongly on the target effect, outcome variability, analysis method, and design assumptions. The numerical illustration values and the observed primary endpoint result are not reported in the registry record, so no quantitative inference about power or required sample size is possible from the information presented.
Why can variability matter?
In general, greater variability makes it harder to estimate a mean precisely and to distinguish a difference from sampling noise. Some outcomes may also have distributions that are more dispersed than a simple model assumes; over-dispersion means that variability exceeds what the model expects. Statistical methods may need to account for that feature when it is present. The registry record does not report an analysis of over-dispersion or identify an alternative variance model. The primary endpoint is continuous and summarized as a mean and standard deviation, but its observed distribution is not reported.
Finally, the record lists five outcome measures and two analyses, but it does not describe the statistical procedures, model specification, handling of repeated observations, confidence interval approach, or analysis software. The absence of these details limits independent assessment of the analytic choices. General statistical concepts can explain what such methods would do, but they cannot establish which methods were actually used in this study.
10. Multiplicity, Missing Data and Analysis Populations
The record lists five outcome measures and two analyses. Multiple outcomes or analyses can raise a multiplicity question: when many statistical tests are conducted, the chance of at least one apparently notable result can increase. In general, a prespecified strategy may identify a primary outcome, distinguish confirmatory from exploratory analyses, or adjust inference across tests. The registry record does not report a multiplicity adjustment, testing hierarchy, or other strategy for addressing multiple comparisons. The primary outcome is identified, but the handling of the remaining outcomes and analyses is not described.
The record names the primary endpoint population as participants with available AUC data. It does not report how many participants had usable measurements, how missing samples or incomplete profiles were handled, or whether any participants were excluded from the endpoint analysis. It also does not state whether missing data were imputed, whether a complete-case approach was used, or how the analysis addressed measurements unavailable at one of the two assessments. These details are not reported in the registry record.
In general, missing observations can affect both precision and the interpretation of a comparison, particularly if availability is related to participant characteristics or the measurements themselves. Without the number and pattern of missing data, it is not possible to assess that issue for this endpoint.
The registry record does not report a full analysis population definition, such as whether all enrolled participants were included in each analysis or whether a different population was used. The listed safety counts include 19 participants at risk in the stated groups, but those counts do not establish the endpoint analysis population. The reason for termination and any implications for planned analyses are also not reported in the registry record.
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 |
|---|---|---|---|
| Etanercept 50 mg Day - 28 - Day 7 | 0 | 19 | 0.0% |
| Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS | 0 | 19 | 0.0% |
| All Subjects On-study | 0 | 19 | 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 |
|---|---|
| Etanercept 50 mg Day - 28 - Day 7 | 13 of 19 |
| Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS | 2 of 19 |
| All Subjects On-study | 13 of 19 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Etanercept 50 mg Day - 28 - Day 7 | Etanercept 50 mg + Denosumab 60 mg Day 8 - EOS | All Subjects On-study |
|---|---|---|---|---|
| Upper respiratory tract infection | Infections and infestations | 3 of 19 | 0 of 19 | 3 of 19 |
| Urinary tract infection | Infections and infestations | 2 of 19 | 0 of 19 | 2 of 19 |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | 2 of 19 | 0 of 19 | 2 of 19 |
| Erythema | Skin and subcutaneous tissue disorders | 2 of 19 | 0 of 19 | 2 of 19 |
| Eye haemorrhage | Eye disorders | 1 of 19 | 0 of 19 | 1 of 19 |
| Diarrhoea | Gastrointestinal disorders | 1 of 19 | 0 of 19 | 1 of 19 |
| Haemorrhoidal haemorrhage | Gastrointestinal disorders | 1 of 19 | 0 of 19 | 1 of 19 |
| Injection site erythema | General disorders | 1 of 19 | 0 of 19 | 1 of 19 |
| Injection site pruritus | General disorders | 1 of 19 | 0 of 19 | 1 of 19 |
| Nodule | General disorders | 1 of 19 | 0 of 19 | 1 of 19 |
The serious adverse event counts list 19 participants at risk and 0 affected in each of the listed periods: etanercept from day -28 through day 7, etanercept plus denosumab from day 8 through end of study, and all subjects on-study. These are counts for the registry’s reported serious adverse event category. They describe what was recorded in those groups and periods, rather than proving that no serious events could occur.
The record also lists 13 participants affected by other adverse events during the etanercept period, 2 during the etanercept plus denosumab period, and 13 across all subjects on-study. These entries should be read in their stated periods; the period counts are not added together to create an overall count. The record does not provide event terms for serious adverse events, and none are listed among the top serious terms.
Deaths are listed as not reported, rather than as a count of zero. The registry record does not provide further detail on event severity, event relationships, duration, or whether participants discontinued because of an event. These safety counts should not be used to infer comparative risk: the study had no randomized control group, and the exposure periods differ.
12. What the Result Does, and Does Not, Mean
This study asks a focused pharmacokinetic question: whether etanercept exposure, summarized by AUC from 0 to 168 hours, differed between its administration alone and its assessment after a single denosumab dose. The registry record describes the population, dosing schedule, assessment timing, and sampling schedule. It does not report the numerical AUC findings, so the size and direction of any observed difference cannot be stated.
The record also does not report numerical results for maximum observed serum concentration or the listed secondary outcomes. Consequently, the available information does not establish whether denosumab changed etanercept pharmacokinetics, nor how precisely any such change was estimated. An absent numerical result is not a result showing no difference.
Even if a numerical contrast were available, the study design would shape its meaning. Because the record describes a single group and no randomized concurrent control, a difference between the day 1 and day 22 assessments would not, by itself, isolate denosumab as the sole explanation. The record’s outcome population is participants with available AUC data, but the number analyzed is not reported, which further limits assessment of completeness.
The study is listed as terminated, with no reason stated in the registry record. That status alone does not explain the outcome findings or safety profile. The serious adverse event entries report 0 affected among 19 at risk in each listed group, while deaths are not reported. These counts are descriptive and do not establish comparative safety.
Accordingly, the registry record supports a careful account of what was planned and how the endpoint was defined, but it does not support a conclusion about the primary pharmacokinetic result. It also does not address clinical effectiveness or provide a basis for medical decisions.
13. Why This Trial Matters Statistically
This trial is statistically instructive because it frames a clearly defined pharmacokinetic endpoint in a small Phase 1, single-group study. The endpoint is an AUC over a stated interval, with scheduled concentration sampling at specified times. Such a design makes the timing and completeness of measurements especially relevant to understanding the estimate.
The record also illustrates why design labels matter. A comparison of measurements taken under two conditions in one group is not equivalent to a randomized comparison between treatment arms. The treatment schedule establishes when denosumab was given, but it does not remove the possibility that changes over time or other factors contributed to differences between assessments. Readers should distinguish a descriptive within-study contrast from a causal estimate supported by randomized control.
Equally important is the distinction between a stated objective and a reported result. The primary question and endpoint are described, yet numerical estimates and uncertainty measures are not reported in the registry record. Without those values, the central statistical question cannot be answered from this record. The omission also prevents readers from judging the observed variability, precision, and practical scale of any pharmacokinetic change.
The listing of 19 enrolled participants alongside an endpoint population defined by available data highlights the need to know how many participants contributed to each analysis and how missing measurements were handled. That information is not reported in the registry record. Finally, the termination status and safety counts need restrained interpretation: neither explains the missing endpoint results, and neither turns the single-group design into a comparative safety study.
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 registry record does not report numerical results for the primary AUC endpoint, including the means, standard deviations, contrast, or confidence interval. It also does not report numerical results for maximum observed concentration or the listed secondary outcomes. This prevents assessment of effect direction, magnitude, and precision.
The study is described as single-group, with no randomized control group. The primary endpoint compares assessments at different times, so time-related changes and other differences between assessments cannot be separated from denosumab exposure by the design information reported. The record does not say whether the planned conduct changed before termination, why the study was terminated, or whether all intended assessments were completed.
Although 19 participants were enrolled, the number contributing available AUC data is not reported. The registry record also does not describe missing-data handling, the analysis population, the statistical model, treatment of repeated measurements, or multiplicity procedures. The sample-size justification and study-specific statistical analysis plan are not reported in the registry record.
Safety information is limited to the listed counts. Deaths are not reported, and detailed event descriptions or comparative analyses are not given. The absence of listed serious adverse events in these counts should be interpreted descriptively, not as proof of no risk. The small enrolled group and absence of a randomized control also limit what these safety data can establish.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Effects of Denosumab on the Pharmacokinetics of Etanercept — NCT01294397.
- Registry record last updated 2017-06-20; status last verified 2017-04.
- Results first posted 2017-06-20.
- 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
NCT01294397 is a Phase 1, single-group study titled Effects of Denosumab on the Pharmacokinetics of Etanercept. It enrolled 19 postmenopausal women with low bone mineral density and rheumatoid arthritis and is listed as terminated. Participants received etanercept 50 mg subcutaneously once weekly for 25 weeks, with a single 60 mg subcutaneous dose of denosumab on study day 8.
The primary endpoint was etanercept AUC from 0 to 168 hours, assessed on day 1 and day 22. The registry record does not report numerical primary endpoint results or the number of participants with available AUC data. It lists 0 serious adverse event cases among 19 at risk in each specified group, and reports other adverse events in the listed periods. Deaths are not reported. The reason for termination and the study’s statistical analysis plan are not reported in the registry record.