Tibial Delayed Healing Pivotal Clinical Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tibial Delayed Healing Pivotal Clinical Trial (NCT01016067), a randomized phase 3 study. The primary outcome is Overall Success.

2. Clinical Question

3. Trial Design

The registry describes a prospective, randomized, multicenter, parallel-group Phase 3 trial comparing INFUSE/MASTERGRAFT with autograft bone. Both groups received rigid internal fixation. The record lists no masking, meaning the trial is described as open-label rather than masked. It was sponsored by Medtronic Spinal and Biologics.

The reported enrollment was 23. The recorded start was 2010-11, and primary completion was recorded as 2013-10. The overall study status is terminated. The reason for termination, whether recruitment ended as planned, and whether the trial reached its intended enrollment are not reported in the registry record. The record does not provide a protocol-level account of randomization procedures, allocation concealment, site-level conduct, or planned follow-up beyond the outcome timeframes listed.

The primary outcome was overall success at 12 Months. Its definition combines radiographic, functional, pain, safety, and additional-surgery criteria. The outcome description reports 10 investigational and 9 control participants evaluable for overall success, compared with 9 investigational and 8 control participants who completed the study at 12-month follow-up. It also says that two subjects were classified as failures because of a related serious adverse event or additional surgery before completion. The record does not fully explain how the evaluable population was determined or how every participant without completion was handled in the primary outcome analysis.

Six secondary outcomes are listed, covering radiographic union, weight bearing, pain, musculoskeletal function, health status, and additional surgery classified as treatment failure. Numeric results are posted for the additional-surgery outcome, but not for the other listed secondary outcomes in the analyses summarized by the record. A formal analysis plan, the rationale for the planned enrollment, and details of any interim monitoring 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Ten investigational and 9 control subjects were evaluable for overall success while only 9 investigational and 8 control subjects completed the study at 12-month follow-up. Two subjects were classified as "failure" due to related serious adverse event or additional surgery before completion of the study.

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 Overall Success, measured over 12 Months.

The primary endpoint, overall success, is a composite participant-level outcome assessed at 12 Months. A participant was counted as successful only if all listed conditions were met: radiographic union success; success in weight-bearing ability; improvement in pain at the delayed healing site; no serious adverse event classified as implant-associated or implant/surgical-procedure-associated; and no additional surgical procedure classified as a failure. Combining these criteria makes the endpoint broader than a radiographic measure alone. It also means that a participant who did not meet any one required component would not meet the composite definition.

Composite endpoints can be used to represent several dimensions of a clinical outcome in one measure. In general, that can make the endpoint responsive to more kinds of outcomes, but it can also make the overall result difficult to interpret without component-level results: the total composite count does not show which criterion most often determined success or failure. The registry lists several related secondary outcomes, but the primary result does not provide component-specific counts for each criterion.

The posted primary counts are 7 successes among 10 evaluable INFUSE/MASTERGRAFT participants and 1 among 9 evaluable autograft participants. The record also distinguishes evaluable participants from those who completed 12-month follow-up. That distinction matters because the endpoint is time-specific and the number analyzed is not identical to the number reported as completing follow-up. The registry record does not report an estimable two-arm comparison for this endpoint, or enough detail to reconstruct the intended primary analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a binary endpoint count?

The primary outcome is binary at the participant level: each participant either met the full overall-success definition or did not. The posted values are counts of participants meeting the definition, paired with the number evaluable in each group. A count is not itself a treatment-effect estimate. To compare groups statistically, an analysis needs a defined contrast and a method for quantifying uncertainty around that contrast. The registry record does not report an estimable two-arm comparison for the primary endpoint.

The secondary additional-surgery outcome is also binary. Its posted counts are 1 of 11 participants in the INFUSE/MASTERGRAFT group and 1 of 12 in the autograft group. For this outcome, the registry gives a risk difference estimate of -0.008 and a confidence interval from -0.238 to 0.223. A risk difference expresses the contrast between the two event probabilities on an absolute scale. In general, the confidence interval communicates uncertainty around that contrast, rather than guaranteeing that the true value lies within the observed interval.

How should the p-value be read?

The secondary comparison has an unadjusted p-value of 0.949. In general, a p-value describes how unusual data at least as inconsistent with a specified null model would be if that model and the analysis assumptions were true. It does not measure the probability that the null hypothesis is true, and it does not measure the probability that the result will reproduce. A large p-value does not establish equivalence or prove that two treatments have identical effects. Here, the confidence interval is also important because it shows that the estimate is imprecise and compatible with a range of possible differences.

The registry labels the p-value as unadjusted. That means it is reported without a stated correction for the fact that several outcomes may be examined. When many outcomes are tested, some apparently notable results can occur by chance even if there is no underlying difference. An adjustment or a clearly prioritized analysis plan can help address that issue. Whether any such plan or adjustment was used is not reported in the registry record.

What do the planning illustrations mean?

The registry includes a planning illustration based on the observed secondary effect, with assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation. It shows participants per arm for 80% and 90% power under scenarios using 100%, 75%, and 50% of the observed effect. The displayed requirements are 21,752 and 29,120 participants per arm for 100% of the observed effect; 39,051 and 52,278 for 75%; and 88,719 and 118,769 for 50%.

These figures are illustrations, not the trial’s enrollment plan and not observed power. The record explicitly describes them as calculations based on the observed effect, rather than the trial’s own design. In general, a sample-size calculation asks how many participants would be needed under specified assumptions to have a chosen chance of detecting a defined effect at a chosen significance threshold. Its result depends strongly on the effect size and other assumptions. A calculation that uses an observed effect can be unstable, particularly when the underlying estimate comes from small groups. The trial’s own sample-size justification is not reported in the registry record.

Why does over-dispersion matter?

Over-dispersion is a general concern for count outcomes when their variability is greater than assumed by a simple model. The primary and posted secondary outcomes in this record are participant counts for binary events, not rate outcomes with a reported dispersion estimate. The record lists no dispersion value for these outcomes. For a binary endpoint, the main analytical considerations instead include the event probabilities, the comparison method, uncertainty, and how missing outcomes are handled. No separate over-dispersion adjustment is reported in the registry record.

What is not available for the primary analysis?

The record lists zero reported analyses for the overall primary outcome and indicates that values were missing or not estimable for a two-arm comparison of the binary endpoint. Therefore, the posted counts should not be mistaken for an adjusted effect estimate or for a complete statistical analysis. The record does not report the primary confidence interval, primary p-value, covariate adjustment, or an analysis population definition beyond the evaluable and completion counts in the outcome description. It also does not report the prespecified test, missing-data method, or whether the analysis followed an intention-to-treat approach.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("INFUSE/MASTERGRAFT", "Autograft Bone")
n      <- c(10, 9)
events <- c(7, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  INFUSE/MASTERGRAFT  10  7  70.0  34.8  93.3  39.7  89.2  39.0  89.1
ARM  Autograft Bone  9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5

11. Multiplicity, Missing Data and Analysis Populations

The primary outcome description separates participants evaluable for overall success from participants completing the 12-month follow-up. It reports 10 investigational and 9 control participants as evaluable, and 9 investigational and 8 control participants as completers. It also states that two subjects were classified as failures because of a related serious adverse event or additional surgery before completion. These details are important because incomplete follow-up can affect which participants contribute to an endpoint and how the result is interpreted.

The registry record does not fully describe the handling of missing outcome data. It does not state whether participants without completed follow-up were counted as failures, excluded, imputed, or handled by another method, apart from the description of the two subjects classified as failures. Nor does it define an intention-to-treat or per-protocol analysis population. The reported evaluable counts and completer counts should therefore be kept distinct; the record does not support assuming that the primary estimate used every enrolled participant or that missing outcomes were handled in a particular way.

Multiplicity is also relevant because several secondary outcomes are listed. In general, testing multiple outcomes without an adjustment can increase the chance of at least one false-positive finding. A prespecified hierarchy, adjustment procedure, or clear separation between confirmatory and exploratory outcomes can help readers understand how to interpret multiple tests. A multiplicity strategy is not reported in the registry record. The secondary additional-surgery p-value is explicitly unadjusted, and the other listed secondary outcomes have no reported analyses.

The registry reports zero analyses for the primary outcome and does not give an estimable two-arm comparison for it. This leaves uncertainty about the planned primary test, the analysis population, and the treatment of missing data. Details of interim analyses and any stopping rules are also not reported in the registry record. The trial’s terminated status is recorded, but the reason for termination and its relationship, if any, to enrollment, follow-up, or analysis are not reported. These omissions limit assessment of whether the posted results correspond to the intended analysis plan.

12. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute myocardial infarction (9.1%), pericardial effusion (9.1%), cellulitis (9.1%), postoperative wound infection (9.1%), incision site pain (9.1%).

The adverse-event record gives serious adverse events for 5 of 11 participants at risk in the INFUSE/MASTERGRAFT group and 3 of 12 in the autograft group. It also gives other adverse events for 7 of 11 and 6 of 12 participants at risk, respectively. These are descriptive participant counts. They should not be treated as a causal comparison: the record does not provide a statistical analysis of these safety figures, and the groups are small.

The record lists Acute myocardial infarction, Pericardial effusion, Cellulitis, Postoperative wound infection, Incision site pain, and Pseudarthrosis among the top serious-event terms, each reported as 9.1%. The registry does not provide enough information in this summary to determine the full event-level distribution, timing, recurrence, or attribution for each term. The primary composite specifically treats serious events classified as implant-associated or implant/surgical-procedure-associated as a failure criterion, but the safety counts alone do not show which events met that classification.

Deaths are not reported in the registry record. Safety counts and event terms describe what was posted; they do not by themselves establish whether one treatment caused more harm or less harm than the other.

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

The posted primary counts show that 7 of 10 evaluable participants in the INFUSE/MASTERGRAFT group and 1 of 9 in the autograft group met the registry’s complete overall-success definition at 12 Months. That definition requires all listed radiographic, weight-bearing, pain, safety, and additional-surgery criteria to be satisfied. These counts describe the participants included in the reported evaluable groups; they are not a complete treatment-effect estimate.

The registry record does not report an estimable statistical comparison for the primary endpoint. Consequently, the primary counts do not provide a posted confidence interval or p-value for the difference, and they should not be presented as proving that either treatment is superior, equivalent, or ineffective. The small group sizes and distinction between evaluable participants and completers further limit how precisely the observed counts can characterize outcomes.

The secondary additional-surgery result is a separate analysis. Its risk difference estimate is -0.008, with a confidence interval from -0.238 to 0.223 and an unadjusted p-value of 0.949. That result is uncertain and does not establish equivalence. It also does not answer the full composite question, because additional surgery is only one component of overall success.

The trial’s terminated status is recorded, but the reason is not reported in the registry record. The posted results also do not include numeric analyses for most of the listed secondary outcomes, a full primary analysis, or a documented missing-data and multiplicity strategy. Those limitations mean that the record offers a partial statistical account rather than a complete basis for drawing broad conclusions about comparative performance or safety.

In general, trial results are interpreted in relation to their design, endpoint definitions, analysis methods, uncertainty, and completeness of follow-up. The reported counts and secondary comparison are useful descriptions of the posted data, but they should be kept within those boundaries. They do not establish a general conclusion beyond the participants and outcomes recorded in this trial.

14. Why This Trial Matters Statistically

This trial is statistically notable because its primary endpoint combines several distinct domains into one success criterion, while the registry does not report an estimable comparison for that endpoint. The distinction between a descriptive count and a treatment-effect estimate is especially important in that setting. The primary counts are available, but the record does not provide the inferential result needed to quantify uncertainty around a between-group contrast.

The population accounting also warrants attention. The record gives separate counts for participants evaluable for overall success and participants completing follow-up at 12 months, and notes two failures before completion due to a related serious adverse event or additional surgery. These details show why analysis-population definitions and follow-up handling matter. Without a complete account of missing outcomes and the intended analysis, readers cannot determine how the posted endpoint counts relate to every enrolled participant.

The secondary additional-surgery analysis illustrates another central biostatistical issue: estimates from small event counts can be highly imprecise. Its confidence interval ranges from -0.238 to 0.223, despite a point estimate of -0.008. In general, uncertainty intervals can be more informative than a p-value alone because they show the range of effect sizes compatible with the data and assumptions. The unadjusted p-value should also be read in light of multiple listed outcomes.

Finally, the sample-size figures are explicitly planning illustrations derived from the observed effect, not the trial’s own design rationale and not observed power. Keeping that distinction clear prevents retrospective planning calculations from being mistaken for evidence about the trial’s operating characteristics. Overall, this record illustrates how outcome definitions, missing-data reporting, multiplicity, and precision all shape what can be learned from a small randomized trial.

15. 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 limitation in interpreting this trial record is the absence of an estimable two-arm analysis for the primary binary endpoint. Although primary success counts are reported, the registry does not provide a primary effect estimate, confidence interval, or p-value. The counts therefore support description but not a precise inferential comparison.

The primary outcome description gives different numbers for participants evaluable for success and participants completing follow-up at 12 months. It also reports two failures before completion. The registry does not fully specify how other incomplete or missing outcomes were handled, how the evaluable population was defined, or whether all randomized participants were analyzed in their assigned groups. That uncertainty affects interpretation of the primary counts.

Numeric results are not reported in the registry record for most listed secondary outcomes. This limits assessment of whether the radiographic, functional, pain, and health-status measures align with the primary composite. The one posted secondary comparison is based on one event in each group, has a broad confidence interval, and is unadjusted. No multiplicity strategy is reported.

The study is listed as terminated, but the reason for termination is not reported in the registry record. The record also does not report the sample-size justification, detailed randomization methods, interim analyses, stopping rules, or full statistical analysis plan. The sample-size figures are retrospective planning illustrations based on the observed secondary effect, rather than documentation of the trial’s original design. These reporting gaps should be kept separate from the observed results: they limit interpretation but do not, by themselves, show why the trial ended or how its conduct affected the outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Tibial Delayed Healing Pivotal Clinical Trial — NCT01016067.
• Registry record last updated 2015-01-21; status last verified 2015-01.
• Results first posted 2014-11-04.
• 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.

19. Record Summary

NCT01016067 is a randomized, open-label, parallel-group Phase 3 trial of INFUSE/MASTERGRAFT with rigid internal fixation compared with autograft bone with rigid internal fixation for tibial delayed healing. The record lists enrollment of 23, a start date of 2010-11, primary completion of 2013-10, and status as terminated.

The primary endpoint was overall success at 12 Months, defined by combined radiographic, weight-bearing, pain, safety, and additional-surgery criteria. The posted counts were 7 of 10 evaluable participants in the INFUSE/MASTERGRAFT group and 1 of 9 in the autograft group. No estimable two-arm analysis is reported for this primary binary endpoint.

The secondary additional-surgery outcome reports 1 of 11 versus 1 of 12 participants, with a risk difference of -0.008, confidence interval -0.238 to 0.223, and unadjusted p-value 0.949. Most listed secondary outcomes have no reported numeric analysis. The record does not report the reason for termination, a full statistical analysis plan, or detailed missing-data methods.