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 Steroids in Bilateral Total Knee Replacement (NCT01399268), a randomized phase 4 study. The primary outcome is Decrease in IL6 Level.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01399268 |
| Phase | Phase 4 |
| Condition | Postoperative Inflammatory Response |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 30 |
| Arms in the primary outcome | 2 |
| Lead sponsor | Hospital for Special Surgery, New York |
| Results posted | Yes |
2. Clinical Question
The trial asks whether continuing low-dose steroids over a 24-hour period changes the inflammatory response to bilateral total knee replacement, with IL6 level as the primary measure. The registry background describes IL6 as a marker of inflammation that increases during total joint replacement surgery. It also explains that the investigators had previously observed a reduction in IL6 after two perioperative steroid doses that was not sustained past 24 hours. The current trial compares a repeated hydrocortisone regimen with saline, assessing IL6 at 24 hours postoperatively.
Population
Participants undergoing bilateral total knee replacement. The registry reports 30 enrolled participants, with 15 in each posted arm. Further participant characteristics and eligibility details are not reported in the registry record.
Intervention
Hydrocortisone 100 mg intravenously every 8 hours for 3 doses. The trial is intended to assess a continued low-dose steroid schedule during the perioperative period.
Comparator
Saline intravenously every 8 hours for 3 doses. The registry identifies the comparison arm as control.
Primary question
What mean IL6 level was recorded 24 hours after surgery in each arm, and how precisely do the posted results characterize any difference between the hydrocortisone and saline groups?
3. Trial Design
This is a completed Phase 4, randomized, parallel-group trial sponsored by Hospital for Special Surgery, New York. The registry lists enrollment of 30 participants. The posted arm results include 15 participants in the steroid group and 15 in the control group. Participants undergoing bilateral total knee replacement were assigned to hydrocortisone or saline; the steroid regimen was hydrocortisone 100 mg IV Q 8hrs x3, and the control regimen was saline IV Q8hr x3.
The registry categorizes masking as quadruple. Which specific people or roles were masked is not reported in the registry record, so the masking label alone does not establish how treatment assignment was concealed from participants, clinical staff, outcome assessors, or analysts. Allocation concealment procedures are also not reported in the registry record. The parallel design indicates that the registry presents separate groups rather than a crossover comparison.
The study start is listed as 2009-02, and primary completion as 2010-08. The record marks the study completed. It does not report the sample-size justification, planned enrollment target beyond the enrollment figure, randomization method, or a full protocol. A statistical analysis plan and any planned interim analyses are not reported in the registry record.
The primary outcome is listed as decrease in IL6 level, measured in pg/ml at 24 hours postoperative. Secondary outcomes include desmosine level, blood glucose, length of hospital stay, in-hospital infection rate, mortality, and ability to ambulate. Six secondary outcomes are posted, while the registry lists seven outcome measures overall. Details of measurement procedures, endpoint definitions, and analysis populations 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.
Overall Study
| Stage | Steroid | Control |
|---|---|---|
| STARTED | 15 | 15 |
| COMPLETED | 15 | 15 |
| NOT COMPLETED | 0 | 0 |
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 | Steroid | Control | Total |
|---|---|---|---|---|
| Participants analysed | 15 | 15 | 30 | |
| Age, Continuous | years | 64 (SD 7) | 71 (SD 9) | 67.5 (SD 8) |
| Sex: Female, Male: Female | Participants | 9 | 6 | 15 |
| Sex: Female, Male: Male | Participants | 6 | 9 | 15 |
| Race and Ethnicity Not Collected | Participants | — | — | 0 |
| Region of Enrollment: United States | participants | 15 | 15 | 30 |
6. Primary Endpoint
The registry lists the primary outcome as Decrease in IL6 Level, measured over 24 hours postoperative.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | 99% Confidence Interval |
| Unit | pg/ml |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is IL6 level at 24 hours after surgery, reported as a mean in pg/ml. IL6 is a cytokine, and the registry background identifies it as a major marker of inflammation that rises during total joint replacement surgery. The investigators’ stated rationale is that reducing the inflammatory response could be relevant to postoperative effects; the registry background discusses associations between elevated IL6 and several postoperative complications. Those background statements explain why IL6 was selected, but they do not establish that IL6 changes in this trial correspond to changes in those outcomes.
The endpoint is reported at a single postoperative time point. It therefore describes IL6 at 24 hours, rather than the full pattern of cytokine release during or after surgery. The registry specifies mean as the summary measure and a 99% confidence interval as the dispersion measure. It does not report a separate primary comparison estimate, confidence interval for the between-arm difference, or p-value. The arm-specific means are 359.4 for steroid and 381.6 for control. The registry gives the same 99% confidence interval limits, 300.0 to 400.0, for both arms. These arm-level summaries do not by themselves provide a direct interval estimate for the difference between groups.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary results are arm-specific mean IL6 levels at 24 hours after surgery: 359.4 pg/ml in the steroid group and 381.6 pg/ml in the control group, with 15 participants in each arm. The steroid-group mean is numerically lower in these summaries. That descriptive ordering is not, by itself, evidence that the groups differ reliably. The registry does not report a primary between-arm estimate, its uncertainty, or a p-value.
Each arm is accompanied by a 99% confidence interval with limits of 300.0 and 400.0. The same limits are listed for both arms. A confidence interval describes uncertainty around an estimate under the analysis used; it is not an interval for the difference between groups unless that contrast is explicitly reported. The arm-level intervals therefore should not be read as a treatment-effect interval, and their shared limits do not demonstrate equivalence.
The secondary results cover different kinds of outcomes. The registry reports group means for continuous outcomes and participant counts for ability to ambulate. Posted unadjusted comparisons include a mean difference for blood glucose and length of stay, and a risk difference for ability to ambulate. These outcomes add context about what was recorded, but the record does not report adjusted analyses or a multiplicity strategy. Their estimates should not be treated as confirmatory evidence of a broader effect, especially when the registry does not identify a prespecified testing hierarchy.
For blood glucose, the posted unadjusted comparison has a mean difference of 31.0, with a confidence interval from 13.55 to 48.45 and p < 0.001. For length of hospital stay, the posted mean difference is 0.0, with p = 1.0. The registry’s ambulation outcome records 1 participant in each arm at 48 hours, with p = 1.0 for the posted unadjusted comparison. These figures describe the posted data and calculations; they do not substitute for a reported analysis plan or a primary IL6 contrast.
For the primary outcome, the most defensible reading is therefore descriptive: the registry presents group means and arm-level intervals, but not the direct inferential comparison needed to quantify the uncertainty around the between-arm IL6 difference. The available results do not establish whether the observed numerical separation reflects a reproducible group difference. They also do not resolve whether any change in IL6 corresponds to changes in clinical outcomes.
9. Statistical Methods Explained
Several statistical ideas help distinguish the posted summaries from a direct test of the trial question. The registry reports descriptive outcome summaries, along with a limited set of unadjusted secondary comparisons. It does not report the sponsor’s full statistical analysis plan, primary between-arm inference, or analysis populations. The estimates should be read in that context.
What a mean describes
A mean is the arithmetic average of the measurements in a group. It gives a compact description of the observed values, but it does not show their full distribution. The primary IL6 outcome is reported as a mean for each arm. The 99% confidence interval is the registry’s accompanying measure of uncertainty around each arm-level result. No standard deviation or other measure of individual variation is reported for IL6, so the range of participant values cannot be reconstructed from the posted primary summaries.
For some secondary outcomes, the registry reports means and standard deviations. A standard deviation describes how dispersed individual observations are around a group mean. It is not the same as a confidence interval for the mean or for a group difference. Continuous outcomes can also be analyzed using a mean difference, which expresses the contrast between group averages in the outcome’s units. The posted secondary mean differences are described as unadjusted recalculations from the summary statistics, not as a substitute for a sponsor-reported analysis.
How to read a confidence interval
A confidence interval expresses uncertainty about an estimate under the assumptions of the method used. It is not a range that contains a fixed proportion of individual participant outcomes, and it does not directly assign a probability to a particular treatment effect. An interval for each arm separately answers a different question from an interval for the contrast between arms. For IL6, the registry gives arm-level 99% confidence intervals with identical limits but no interval for the between-arm difference. Consequently, those arm-level intervals cannot be used as the direct uncertainty estimate for the randomized comparison.
What an unadjusted p-value means
A p-value summarizes how incompatible the observed data are with a specified null hypothesis, under the statistical model and testing procedure used. It is not the probability that the null hypothesis is true, nor does it measure the size or importance of an effect. The posted p-values for secondary comparisons are unadjusted. This means they are reported without a stated correction for examining multiple outcomes or comparisons. Because the registry does not report a multiplicity plan, the p-values should not be interpreted as if a prespecified family of tests and decision rule were documented.
A small p-value can coexist with uncertainty about generalizability, measurement, analysis choices, and clinical relevance. A large p-value does not establish that groups are equivalent. The trial’s primary IL6 result has no posted between-arm p-value, so the secondary p-values cannot answer the primary question.
Binary outcomes and sparse counts
Ability to ambulate is recorded as a participant count at 48 hours. A risk difference compares the proportions with the outcome between groups. When event counts are small, the estimate can be imprecise, and a lack of a detected difference does not establish equal underlying risks. The registry reports one participant with the outcome in each arm and a risk-difference estimate of 0.0. The posted interval for that comparison is not repeated because it has more than three decimal places; the important interpretive point is that sparse counts provide limited information about a group contrast.
In general, over-dispersion matters when observed variation exceeds what a model assumes. In that situation, model-based standard errors and confidence intervals can be too narrow if the extra variation is not accounted for. The registry does not report a distributional assessment or a model for the primary outcome, so whether over-dispersion was evaluated is not reported in the registry record. This is a general statistical consideration, not a claim about the trial’s data.
Planning illustrations are not observed power
The registry includes a planning illustration based on the observed blood-glucose effect. It states assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation. The illustration considers planning for 100%, 75%, and 50% of the observed effect and gives participants per arm for 80% and 90% power. These are hypothetical planning quantities derived from the observed effect, not the trial’s original sample-size calculation and not observed power. The sample-size justification for the actual trial is not reported in the registry record. Using an effect estimated in a small study for planning can also produce unstable illustrations; the figures do not show what the trial was designed to detect.
More generally, a trial’s analysis is best understood through its prespecified outcome definitions, estimand, model, missing-data procedures, and population for analysis. Those details are not reported in the registry record. The posted summaries permit description of the recorded outcomes and some simple comparisons, but they do not disclose all the choices needed to reproduce or fully assess the trial’s statistical analysis.
10. Multiplicity, Missing Data and Analysis Populations
The registry record does not report how the investigators handled multiplicity across the primary and secondary outcomes. It lists several outcome measures and posts unadjusted secondary comparisons, but does not state whether the analyses followed a prespecified hierarchy, whether any outcomes were considered exploratory, or whether p-values were adjusted. Without this information, the secondary p-values should not be interpreted as a family-wise set of confirmatory tests. The registry also does not report whether an interim analysis was planned or conducted.
Missing-data procedures are not reported in the registry record. The posted outcome summaries give group counts for selected results, but do not describe participant flow, withdrawals, missing measurements, or how missing values were handled. Equal posted arm counts do not establish that every randomized participant contributed data to every outcome. Reasons for any discrepancy between enrollment and outcome-specific analysis populations are not reported.
The analysis population is not reported in the registry record. It is therefore unclear from the registry whether the outcome summaries use all randomized participants, participants who received assigned treatment, or another defined group. The record does not state how treatment deviations were handled or whether an intention-to-treat approach was used. These are important features of a randomized trial analysis because they clarify which participants contribute to each estimate and how the original assignment is preserved in analysis.
The protocol, detailed analysis plan, sample-size justification, and methods for handling multiple endpoints are not reported in the registry record. The planning illustration based on the observed blood-glucose effect is not evidence of the trial’s original design assumptions. These omissions limit assessment of whether the posted outcomes and analyses match prespecified methods, and they prevent a full evaluation of selective outcome reporting or robustness to missing-data assumptions.
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 |
|---|---|---|---|
| Steroid | 0 | 15 | 0.0% |
| Control | 0 | 15 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Steroid | 0 of 15 |
| Control | 0 of 15 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Steroid | 0 of 15 |
| Control | 0 of 15 |
The registry reports zero serious adverse events among 15 participants at risk in the steroid group and zero among 15 at risk in the control group. It also reports zero other adverse events in each group, with 15 participants at risk per group, and zero deaths in both arms. No serious adverse-event terms are listed.
These counts mean that no events in the listed categories were recorded in the posted results for the participants counted as at risk. They do not establish that the treatments have no risk or that the groups have identical safety profiles. With a small number of participants, uncommon events may not occur during observation even when a risk exists. The record does not report the adverse-event collection period, event definitions, severity grading beyond the serious-event category, or methods for assessing causality. The zero counts should therefore be read as a description of observed reports, not as proof of safety or evidence that one regimen is safer than the other.
12. What the Result Does, and Does Not, Mean
The registry result describes a randomized comparison of hydrocortisone and saline in people undergoing bilateral total knee replacement. At 24 hours after surgery, the posted mean IL6 level is 359.4 pg/ml in the steroid group and 381.6 pg/ml in the control group. These group summaries show a numerical difference in the observed means, but the registry does not report a direct estimate or confidence interval for the between-arm difference. The posted primary data therefore do not establish how precisely the groups differ.
The result does not show that a change in IL6 produced a change in postoperative complications, lung injury, or other clinical outcomes. The registry background describes prior observations and biological rationale, but the posted primary outcome is IL6 at a single time point. Secondary outcomes provide additional observations, yet the registry does not report a multiplicity plan or complete inferential analysis for all listed outcomes. Those data cannot support a definitive broad conclusion about clinical benefit.
Nor does a non-significant secondary comparison, where reported, demonstrate that the groups are equivalent. Equivalence requires an appropriate design and a prespecified margin, neither of which is reported in the registry record. Similarly, a small p-value for a secondary outcome does not by itself establish clinical importance or settle the primary question.
The results should be interpreted within the trial’s scope: a small randomized study in bilateral total knee replacement, with 15 participants per posted arm and incomplete reporting of key statistical methods. They are descriptive evidence about the outcomes recorded in this trial. They do not justify advice for individual care, establish effects in other surgical settings, or resolve uncertainty about the primary treatment contrast.
13. Why This Trial Matters Statistically
This trial is statistically instructive because it illustrates the difference between reporting group summaries and reporting the randomized comparison. The primary endpoint is central to the stated question, yet the registry gives an arm-specific mean and confidence interval for each group without a direct contrast estimate or its uncertainty. Readers need the contrast to assess how much the observed groups differ and how precise that estimate is.
It also illustrates why endpoint timing matters. The primary measure is IL6 at 24 hours postoperative, while the investigators’ rationale concerns cytokine release and whether a reduction is maintained. A single time point provides a limited view of a biological process that may vary over time. The registry does not report a longitudinal analysis or the details needed to assess changes across multiple measurements.
The secondary results highlight a separate issue: unadjusted analyses across several outcomes can be difficult to interpret without a prespecified testing strategy. A collection of endpoint-specific p-values is not equivalent to a single confirmatory test. Clear reporting of the analysis plan, analysis population, missing-data approach, and multiplicity handling would help readers understand which conclusions were planned and how uncertainty was controlled.
Finally, planning illustrations based on an observed effect should be distinguished from the original design rationale. They can show how hypothetical sample sizes vary under stated assumptions, but they do not establish the trial’s initial target or its ability to answer the primary question. This distinction is especially important when a small study’s observed effect is used as the basis for planning.
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 principal trial-specific limitation is the small enrollment: 30 participants, with 15 in each posted arm. Estimates from a small study can be imprecise, particularly for outcomes recorded as infrequent events. The registry’s primary IL6 summaries do not include a direct between-arm estimate or confidence interval, so the uncertainty relevant to the main comparison cannot be assessed from the primary result alone.
The primary outcome is reported at 24 hours postoperative. The registry background discusses peak IL6 release and whether a reduction is maintained, but a single reported time point cannot describe the full cytokine trajectory. The registry record does not report the timing of any additional IL6 measurements, or whether they were analyzed. The primary measure is a biomarker; the posted result does not by itself establish a change in clinical outcomes.
The population is limited to people undergoing bilateral total knee replacement. Participant characteristics and further eligibility details are not reported in the registry record, which limits assessment of how similar the enrolled participants may be to other clinical populations. The study’s sponsor is Hospital for Special Surgery, New York, but the number and locations of study sites are not reported in the registry record.
Interpretation is further limited by missing reporting on the analysis plan, sample-size justification, analysis populations, missing data, and multiplicity. Some listed secondary outcomes do not have posted results, and the record does not state why. The registry also does not report the specific roles covered by quadruple masking or the procedures used to maintain masking. These reporting gaps do not show that the methods were inadequate; they mean that their adequacy cannot be assessed from the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Steroids in Bilateral Total Knee Replacement — NCT01399268.
- Registry record last updated 2017-07-31; status last verified 2017-07.
- Results first posted 2017-07-31.
- 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
NCT01399268, titled “Steroids in Bilateral Total Knee Replacement,” is a completed randomized, quadruple-masked, parallel Phase 4 trial sponsored by Hospital for Special Surgery, New York. It enrolled 30 participants undergoing bilateral total knee replacement and compared hydrocortisone with saline. The posted groups each contain 15 participants.
The primary outcome is mean IL6 level at 24 hours postoperative. The registry reports arm-specific means and 99% confidence intervals, but no direct between-arm primary estimate or p-value. Six secondary outcomes are posted, including selected unadjusted comparisons. Serious adverse events, other adverse events, and deaths are each reported as zero in both arms.
The registry record does not report the primary analysis plan, sample-size justification, analysis populations, missing-data methods, or multiplicity strategy. These gaps limit statistical interpretation beyond the descriptive posted results.