Total Knee Replacement Component Alignment Using Manual Versus Custom Instrumentation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Total Knee Replacement Component Alignment Using Manual Versus Custom Instrumentation (NCT02579174), a randomized na study. The primary outcome is Post-Operative Hip-Knee-Angle (HKA).

2. Clinical Question

3. Trial Design

This was a randomized study with a factorial model and single masking, with enrollment of 112. The registry does not identify who was masked, describe the randomization procedure, or provide further details about how the factorial assignments were generated. The study status is completed. Its listed intervention was the Medacta GMK Sphere device for total knee replacement.

The factorial assignments varied instrumentation independently across the tibial and femoral components: manual for both, custom for both, manual tibial with custom femoral, and custom tibial with manual femoral. This structure makes it possible to describe outcomes by component-specific instrumentation as well as to compare the two groups that used the same type for both components. The primary endpoint population was restricted to those same-type groups, rather than including the mixed assignments.

The study summary describes three aims: assessing whether EOS has accuracy comparable to CT, validating EOS as a tool for evaluating three-dimensional implant alignment, and evaluating alignment differences between manual and custom instrumentation. The posted primary outcome is a change in hip-knee-angle measured using EOS. The registry does not report the results of an EOS-versus-CT accuracy analysis or a separate validation analysis.

Primary endpoint values are available for 18 participants in the total-component-manual group and 16 in the total-component-custom group. The secondary endpoint comparisons use groups of 34 and 32. These outcome-specific counts do not by themselves explain who contributed data, how participants were selected for each analysis, or why the sizes differ. Those details are not reported in the registry record. The listed randomization, factorial structure, and masking designation describe the design, but they do not establish which analysis population or statistical model was used.

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

Analysis population for the primary outcome, as defined in the registry: Sub group analysis of only participants who received both manual or both custom instrumentations.

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.

6. Primary Endpoint

The registry lists the primary outcome as Post-Operative Hip-Knee-Angle (HKA), measured over Pre-operative, 6 wks. post-op.

The primary endpoint is postoperative hip-knee-angle change, expressed in degrees. The registry describes the measure as the change from a preoperative EOS longstanding X-ray to postoperative EOS at 6 weeks. The values are reported as means with standard deviations. The population is a subgroup of participants who received manual instrumentation for both components or custom instrumentation for both components.

The endpoint is used to describe alignment change following total knee replacement and to compare the two same-type instrumentation groups. Its definition ties the measurement to a specified imaging method and follow-up time, which is important when interpreting what the outcome represents: it is not a general measure of every aspect of the operation or recovery. The registry summary also identifies EOS as a focus of the study, including its comparison with CT and its proposed use for assessing three-dimensional implant alignment. However, the posted primary endpoint is specifically the HKA change measured with EOS; it is not itself a reported accuracy comparison between EOS and CT.

The registry reports a mean of 2.14 degrees with a standard deviation of 1.79 for total component manual instrumentation, and a mean of 3.06 degrees with a standard deviation of 2.33 for total component custom instrumentation. It does not provide a formal primary between-group estimate or interval. Without those, the descriptive group values do not establish the precision of the contrast.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports continuous outcomes as means and standard deviations. A mean describes the average observed value in a group; a standard deviation describes how dispersed individual values are around that group average. The standard deviation is not the same as uncertainty in the group mean, and neither summary alone gives the uncertainty in a between-group difference. The primary endpoint values are descriptive summaries, not a reported formal treatment-effect estimate.

What does a mean difference express?

A mean difference compares the group averages on the outcome's original scale. For the secondary outcomes, the recalculated estimates compare custom instrumentation with manual instrumentation in the component-specific groups described in the registry. For example, the tibial outcomes compare groups defined by tibial instrumentation, while the femoral valgus outcome compares groups defined by femoral instrumentation. The sign depends on the order of the groups in the comparison. A positive or negative estimate describes which group mean is larger under that ordering; it does not, by itself, describe clinical importance.

The secondary mean differences were recalculated from the posted group summaries. They are simple, unadjusted comparisons, not estimates from a model that adjusts for other variables or accounts for the factorial structure. The registry does not report sponsor analyses for these secondary endpoints. The recalculated estimates are therefore useful as a transparent reading of the posted means, but they should not be mistaken for a prespecified or sponsor-reported analysis.

How should confidence intervals be read?

A confidence interval expresses uncertainty around an estimate under the assumptions of the method used to construct it. For a mean difference, an interval that includes zero is compatible with a range of possible differences that includes no difference as well as differences in either direction. It does not prove that the groups are the same. A wide interval indicates less precision than a narrow one, though whether any range is clinically important depends on a threshold that the registry does not report.

The recalculated intervals for the secondary outcomes include zero. That observation should be interpreted alongside their point estimates and p-values, not as a definitive conclusion about equality. The primary endpoint has no reported between-group interval in the registry record, so the precision of its contrast is not directly available. The reported standard deviations cannot substitute for a confidence interval on the between-group effect.

What do the p-values say?

A p-value is a measure of how unusual data at least as discrepant as those observed would be under a specified null model and its assumptions. It does not give the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The unadjusted p-values for the secondary recalculations are 0.133 for tibial varus deformity, 0.461 for femoral valgus deformity, and 0.513 for tibial posterior slope. The registry does not post a primary p-value. Because the secondary tests are unadjusted, their p-values do not account for the fact that multiple outcomes were examined.

Why does the factorial structure matter?

Instrumentation was assigned separately for the tibial and femoral components, producing both same-type and mixed-type combinations. A factorial design can, in general, be analyzed to estimate component-specific effects and interactions between factors. But that general possibility does not reveal which model was planned or used in this study. The registry identifies the model as factorial, while a full statistical model, interaction analysis, and allocation details are not reported. The primary analysis is explicitly a subgroup comparison of participants receiving both manual or both custom instrumentation; it should not be treated as an analysis of all factorial assignments.

Component-specific secondary comparisons use the listed groups for each endpoint. The registry does not explain whether these comparisons were adjusted for the other component's instrumentation or whether interactions were considered. Consequently, the recalculated comparisons should be understood as simple summaries based on the reported groups, not as a complete factorial analysis.

What are the planning illustrations?

The sample-size illustrations use the observed effect as a planning reference, with the assumed effect set at 100%, 75%, or 50% of that observed effect. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For continuous outcomes, the displayed counts are participants per arm for 80% or 90% power. These are hypothetical planning illustrations based on observed effects, not observed power and not evidence about the study's original design. The registry does not report its own sample-size justification or assumptions. The primary endpoint lacks a reported formal contrast from which a comparable planning illustration could be grounded.

More generally, planning calculations based on an observed effect are sensitive to how accurately that effect represents the effect a future study aims to detect. Smaller assumed effects require larger planned groups under otherwise similar assumptions. This is a general statistical principle, not a claim about the original trial's planning. No over-dispersion adjustment or other specialized model is described in the registry record, and no such adjustment should be inferred.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan, a multiplicity adjustment, interim analyses, or a formal primary comparison. It lists three secondary outcomes, each with a recalculated unadjusted comparison, and no reported analyses for those outcomes. Without a stated testing hierarchy or adjustment procedure, the secondary p-values should not be treated as if they controlled the overall chance of false-positive findings across the outcomes. The record also does not indicate whether other analyses were planned but not posted.

Missing-data handling is not reported in the registry record. The primary endpoint group sizes are 18 and 16, whereas the secondary comparisons list group sizes of 34 and 32. These counts alone do not show whether participants lacked measurements, were excluded, or belonged to different analysis populations. The record does not provide a flow of participants from enrollment through each endpoint analysis, reasons for unavailable values, imputation methods, or sensitivity analyses.

The registry identifies the primary population as a subgroup receiving both manual or both custom instrumentation. It does not state whether this was an intention-to-treat analysis, a per-protocol analysis, or another defined analysis population. The record does not describe how deviations from assigned instrumentation or other protocol events were handled. The single-masking designation does not identify who was masked or whether outcome assessment was masked.

The study is labeled factorial, but the registry does not report the statistical model, whether interaction terms were examined, or how the mixed instrumentation assignments entered the primary analysis. No sample-size justification from the trial's own design is reported. The planning illustrations based on observed effects are not evidence of the original planned sample size or power. These gaps limit assessment of prespecification, missingness, and the scope of the analyses.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry lists four instrumentation combinations for the adverse-event summaries. In the manual tibia and manual femur group, 18 participants were at risk for serious adverse events and none were reported; 18 were at risk for other adverse events and none were reported. For manual tibia and custom femur, the corresponding at-risk counts were 16 and 16, with no serious or other adverse events reported. For custom tibia and custom femur, the at-risk counts were 16 and 16, again with zero reported serious and other adverse events. For custom tibia and manual femur, the at-risk counts were 16 and 16, also with zero reported events of either category. No deaths were reported in any group.

These figures describe the registry's posted counts, not proof that no adverse events occurred outside the recorded reporting process. The record does not provide event definitions, the safety observation period, methods for collecting events, or a detailed account of ascertainment. With no reported events, the summaries cannot establish that the groups have identical safety profiles or exclude events that were not captured. They should be read as zero reported events among the listed at-risk participants, within the information documented by the registry.

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

The posted results describe alignment measurements after total knee replacement using manual or custom instrumentation. The primary endpoint summaries give average HKA change for two groups receiving the same instrumentation type for both components. The group means are 2.14 degrees and 3.06 degrees, with standard deviations of 1.79 and 2.33, respectively. Because no formal primary contrast, confidence interval, or p-value is reported, the record does not establish how precisely the groups differ on this outcome.

The secondary recalculations add estimated mean differences and uncertainty intervals for component-specific alignment measures. Their intervals include zero, and the comparisons are unadjusted. These findings do not demonstrate equivalence, rule out potentially important differences, or establish a treatment effect. The registry does not report a threshold for clinical importance, so statistical summaries alone cannot determine whether an observed difference would matter clinically.

The study summary also describes aims concerning EOS and CT, including assessing EOS accuracy and validating it for three-dimensional alignment evaluation. Those aims should be distinguished from the posted primary HKA result. EOS-versus-CT accuracy results and a separate validation result are not reported in the registry record.

Similarly, the absence of reported adverse events in the listed groups should not be interpreted as proof of zero risk. It means only that the registry reports no events in those summaries. Follow-up and event-collection details are not reported, and the endpoint-specific participant counts do not explain all aspects of data availability.

Overall, the record offers descriptive primary values, exploratory secondary recalculations, and sparse safety counts. It does not contain enough reported inferential or methodological detail to support a broad conclusion about the relative performance of the instrumentation approaches. The results are best understood within the specific endpoints, populations, and reporting limitations described.

13. Why This Trial Matters Statistically

This trial is statistically interesting because it combines a factorial instrumentation structure with multiple ways of measuring component alignment. The tibial and femoral components could each receive manual or custom instrumentation, while the primary endpoint focuses on participants receiving the same type for both components. That distinction matters: a same-type subgroup contrast is not automatically equivalent to a full factorial analysis that separates component effects or examines interaction.

The registry also illustrates why endpoint summaries and inferential results are not interchangeable. Means and standard deviations describe each primary group, but without a reported primary contrast and interval they do not communicate the uncertainty of the between-group estimate. The secondary recalculations show how an unadjusted estimate and confidence interval can add context, while also underscoring that such calculations are not a substitute for a prespecified analysis.

Another statistical issue is the separation between the study's stated imaging aims and its posted outcome results. The summary identifies EOS-versus-CT accuracy and validation questions, but the posted primary endpoint is an EOS-measured HKA change. A measurement endpoint may be relevant to a broader validation goal, but it does not itself provide the comparative accuracy result. Clear alignment between the research question, outcome, analysis population, and reported estimate is essential for interpretation.

Finally, the registry's limited detail on missing data, multiplicity, and factorial modeling demonstrates how reporting affects the strength of statistical interpretation. A completed trial can still leave uncertainty about how its planned analyses were conducted. Readers need the analysis population, model, assumptions, and uncertainty estimates to judge the reliability and scope of a result.

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 main trial-specific limitation is that the registry reports only descriptive group summaries for the primary HKA endpoint. It does not report the primary between-group effect estimate, confidence interval, or p-value. This prevents direct assessment of the primary contrast's precision and leaves the descriptive means as the only posted primary comparison information.

There is also a mismatch between total enrollment and the endpoint-specific group sizes, without an explanation of participant flow or missing measurements. The primary endpoint is restricted to the two same-type instrumentation groups, while secondary comparisons use component-specific groups with different listed counts. The record does not establish why those populations differ or how selection into each analysis may affect interpretation.

The registry labels the study factorial but does not report the model used, the handling of mixed assignments in inferential analyses, or tests of interactions. The secondary estimates are unadjusted recalculations, and no multiplicity approach is described. The registry does not report its own sample-size rationale, a protocol-level statistical analysis plan, or whether the listed analyses were prespecified.

The study summary includes EOS-versus-CT accuracy and validation aims, but corresponding results are not reported in the registry record. Safety reporting is also limited: event counts are listed, but event definitions, observation periods, and ascertainment procedures are not described. These limitations are specific to what the registry records and should not be taken as evidence about analyses or data that may exist outside the record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Total Knee Replacement Component Alignment Using Manual Versus Custom Instrumentation — NCT02579174.
• Registry record last updated 2022-11-15; status last verified 2022-10.
• Results first posted 2022-11-15.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The completed randomized study enrolled 112 participants and evaluated total knee replacement with manual or custom instrumentation for the tibial and femoral components. Its primary outcome was preoperative-to-6-week postoperative HKA change measured using EOS, in a subgroup receiving manual instrumentation for both components or custom instrumentation for both components. The registry reports group means and standard deviations, but no formal primary contrast or uncertainty interval.

Three secondary alignment outcomes have unadjusted recalculated comparisons. Their confidence intervals include zero. The registry lists no serious adverse events, other adverse events, or deaths in the reported instrumentation groups. Statistical analysis details, missing-data methods, multiplicity handling, participant flow, and EOS-versus-CT accuracy results are not reported in the registry record.