The Effect of Bone-void Filler on Anterior Knee Pain Following ACL Reconstruction: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Effect of Bone-void Filler on Anterior Knee Pain Following ACL Reconstruction (NCT04533880), a randomized na study. The primary outcome is Score on Knee Injury and Osteoarthritis Outcome Score (KOOS) Survey.

2. Clinical Question

The clinical question concerns whether adding either demineralized bone matrix or calcium phosphate cement to autologous bone is associated with a different Month 12 Post-Op KOOS mean score than using autologous bone alone after ACL reconstruction with bone-patellar tendon bone autograft. The registry record describes anterior knee pain as a common complaint after this procedure and identifies the bone defect left by graft harvesting as a possible contributor. It also notes that there is no consensus on a gold standard for filling that defect.

The recorded primary outcome is a broad patient-reported score covering symptoms, pain, daily function, sports and recreation function, and quality of life. It is not described as an isolated measure of anterior knee pain. Thus, the outcome speaks to the reported KOOS score at the stated follow-up, while the trial’s stated motivation concerns anterior knee pain and the graft-harvest bone defect. The record does not report a separate primary anterior-knee-pain score.

3. Trial Design

The registry record identifies this as a randomized, parallel-group trial with no masking. It lists three groups: control with autologous bone from the graft harvest, autologous bone plus demineralized bone matrix, and autologous bone plus calcium phosphate cement. The record does not describe the randomization procedure, allocation concealment, or whether any people assessing outcomes were masked.

Enrollment is listed as 150. The posted primary outcome results include 52 participants for control, 49 for autologous bone plus demineralized bone matrix, and 47 for autologous bone plus calcium phosphate cement. Those figures are the group counts attached to the reported outcome; the registry record does not explain the relation between the enrollment figure and the outcome counts or describe participant flow.

The trial status is completed. The listed start date is 2020-08-31, and the primary completion date is 2023-07-07. NYU Langone Health is identified as the sponsor. The phase field is listed as NA. No trial-specific sample-size justification or original design assumptions are reported in the registry record.

The primary outcome is a continuous KOOS score at Month 12 Post-Op. The posted results give a mean and standard deviation for each group. Pairwise comparisons are against control, and the displayed estimates are mean differences. No secondary outcome results are posted, and the registry record reports no analyses. These limitations leave the reader with the stated group summaries and the available comparison statistics rather than a fuller account of the prespecified analysis or participant disposition.

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:

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 Score on Knee Injury and Osteoarthritis Outcome Score (KOOS) Survey, measured over Month 12 Post-Op.

The primary endpoint is the Score on Knee Injury and Osteoarthritis Outcome Score (KOOS) Survey at Month 12 Post-Op. The survey comprises 42 questions arranged in five sub-categories: symptoms, pain, function/daily living, function/sports and recreational activities, and quality of life. The record states that each item is rated on a Likert scale from 0 to 4. It reports a total range of 0-500 for the whole survey and says that higher scores indicate worse symptoms and pain or greater difficulty in function.

This endpoint is used to collect patient-reported information across several aspects of knee symptoms and function rather than relying only on a single clinical observation. Its pain sub-category is relevant to the trial’s stated concern about anterior knee pain, while the additional domains capture wider aspects of the knee experience. The registry record does not give a separate score for the pain sub-category or an isolated anterior knee pain measure. The posted primary results therefore concern the overall KOOS score as described in the record, not a separately reported pain-domain result.

For each group, the record reports the mean score and standard deviation. Since higher scores are described as worse, a higher group mean corresponds to a less favorable score on this scale. The reported group means are 67.0 for control, 69.0 for autologous bone plus demineralized bone matrix, and 67.7 for autologous bone plus calcium phosphate cement.

7. Results Posted in the Registry

• Autologous Bone + DBM: mean 69.00 versus 67.00 on control; difference 2.00 (95% CI -0.42 to 4.42), standardized effect d = 0.32; z-test p = 0.105.
• Autologous Bone + Calcium Phosphate Cement: mean 67.70 versus 67.00 on control; difference 0.70 (95% CI -2.17 to 3.57), standardized effect d = 0.10; z-test p = 0.633.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary result is a continuous outcome summarized by a mean and standard deviation in each group. The mean describes the center of the observed scores, while the standard deviation describes their spread around that mean. General statistical explanation: a standard deviation is a measure of variability among individual observations; it is not the uncertainty of the group mean itself. The group standard deviations were 6.1 for control, 6.3 for autologous bone plus demineralized bone matrix, and 8.2 for autologous bone plus calcium phosphate cement.

What does a mean difference express?

A mean difference subtracts the control-group mean from the comparison-group mean. The posted comparison for autologous bone plus demineralized bone matrix is 2.0, and the posted comparison for autologous bone plus calcium phosphate cement is 0.7. Positive values mean the comparison-group mean is numerically higher than the control mean. Since the record describes higher KOOS scores as worse, the direction is toward a higher, less favorable score on the recorded scale; this is a direction-of-score description, not proof of a meaningful effect.

What does a confidence interval add?

General statistical explanation: a confidence interval gives a range of values compatible with the data and the method used to calculate it. A wide interval signals greater uncertainty about the estimated difference; an interval that includes zero is compatible with no mean difference as well as with nonzero differences in either direction. Both posted comparison intervals include zero. The record does not state a threshold for a clinically important KOOS difference, so statistical uncertainty cannot be translated into a judgment about clinical importance from these data alone.

How should the p-values be read?

The unadjusted p-values are 0.105 for demineralized bone matrix plus autologous bone versus control and 0.633 for calcium phosphate cement plus autologous bone versus control. General statistical explanation: a p-value describes how unusual data at least as incompatible with a null hypothesis would be under the assumptions of a specified statistical test. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference. These are unadjusted values; the registry record does not report a multiplicity adjustment or a detailed analysis plan.

What is the role of unadjusted comparisons?

The two comparisons use control as the reference group and report mean differences with confidence intervals and unadjusted p-values. No covariate-adjusted estimates are reported in the registry record. These are comparisons between group summaries, and they do not show whether any other variables were balanced or how potential differences in participant characteristics were handled. The record reports no analyses beyond the posted comparison results, so further model details, diagnostic checks, or adjusted analyses are not reported in the registry record.

Why can variation affect interpretation?

General statistical explanation: greater variability in scores makes a group mean less precise when other factors are held constant. Variation also matters when estimating a difference between group means, because the estimate depends on the variability and the number of observations contributing to each group summary. The observed standard deviations differ across the three groups, with the largest reported in the calcium phosphate cement group. The posted standard deviations describe the observed score spread; they do not explain its source.

General statistical explanation: over-dispersion occurs when observations vary more than a model or analysis assumes. In a continuous-outcome comparison, a mismatch between the variability in the data and the assumptions used for inference can affect standard errors and confidence intervals. The registry record does not report a test of distributional assumptions, a model specification, or checks for over-dispersion. No claim about those checks can therefore be made.

The record identifies a randomized design, but the group summaries alone do not document the randomization process or its implementation. It also identifies no masking. Details of allocation concealment, outcome assessment, missing-data handling, and the analysis population are not reported in the registry record. Those omissions limit the ability to assess how the results were generated and how robust they may be to alternative analysis choices.

The comparison results should be read alongside the stated score direction: higher KOOS values are worse according to the record. They should also be read as estimates with uncertainty, rather than as definitive statements about benefit, harm, equivalence, or the absence of an effect. The registry record does not report a minimally important difference, so the practical importance of a given numerical difference is not established.

10. Confidence Intervals and Precision

The mean difference estimate for autologous bone plus demineralized bone matrix versus control is 2.0, with a confidence interval extending from a negative value to a positive value. For autologous bone plus calcium phosphate cement versus control, the estimate is 0.7, and its confidence interval also extends from a negative value to a positive value. Both intervals include zero. This means that the posted estimates are compatible with no mean difference and also with differences in either direction.

The intervals are not so narrow that they settle the size of the between-group differences. The positive point estimates alone do not show that the interventions produced worse scores, just as inclusion of zero does not establish that there is no difference. The uncertainty is especially important because the registry record does not report a threshold for a clinically important difference on the overall KOOS scale.

Confidence intervals are generally more informative than a binary reading of a p-value because they display the range of plausible values under the calculation method. Here, both unadjusted p-values are above the 0.05 significance level used in the sample-size planning illustration, but that planning assumption does not establish the trial’s own testing threshold. The registry record does not report the original analysis plan or a prespecified decision rule.

The interval estimates depend on the posted group summaries and the comparison method. The registry record does not provide further details about adjustment, missing outcomes, or analysis populations. Thus, precision should be understood as precision of the posted comparisons, not as assurance that all sources of uncertainty have been addressed.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size illustrations are planning calculations based on the observed effect, not the trial’s original design assumptions. For these continuous-outcome comparisons, the displayed quantities are participants per arm, not total events. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. The trial’s own sample-size justification and original planning assumptions are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm for a design that would have an 80% chance of detecting the selected effect under the stated assumptions, if that effect and those assumptions were correct. The 90% power column gives the corresponding planning figure for a higher chance of detecting that selected effect. These are design illustrations, not evidence about the chance that the completed trial detected an effect.

For the demineralized bone matrix comparison, planning for 100% of the observed effect gives 151 participants per arm for 80% power and 202 for 90% power. Planning for 75% of the observed effect gives 268 participants per arm for 80% power and 359 for 90% power. Planning for 50% of the observed effect gives 603 participants per arm for 80% power and 808 for 90% power.

For the calcium phosphate cement comparison, planning for 100% of the observed effect gives 1,649 participants per arm for 80% power and 2,207 for 90% power. Planning for 75% of the observed effect gives 2,931 participants per arm for 80% power and 3,923 for 90% power. Planning for 50% of the observed effect gives 6,594 participants per arm for 80% power and 8,827 for 90% power. Smaller effects need more participants to detect under the stated assumptions. These are planning illustrations and are not observed power.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 2.000; pooled standard deviation σ = 6.198.
2. n = 2 × (1.96 + 0.842)² × 6.198² / 2.000² = 150.7, rounded up to 151 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 2                      # observed difference in means
sigma <- 6.19777574960762                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(4533880)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 151 (80% power), 202 (90% power)
 75% of observed effect: n per arm = 268 (80% power), 359 (90% power)
 50% of observed effect: n per arm = 603 (80% power), 808 (90% power)
power.t.test: 151.7 
Simulated power at n = 151 per arm: 0.798 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The results include two pairwise comparisons with control: autologous bone plus demineralized bone matrix and autologous bone plus calcium phosphate cement. The record presents unadjusted p-values for both. It does not report whether the comparisons were prespecified as a family, whether an adjustment for multiple comparisons was planned, or how any such adjustment would be made. Because the analysis plan is not reported in the registry record, the implications of examining multiple comparisons cannot be fully assessed.

The record reports no secondary outcome results, although it lists three outcome measures. Details about the other measures are not posted among the results. The registry record also reports no analyses. It does not identify a primary analysis population, such as an intention-to-treat or per-protocol population, and does not explain whether all randomized participants were included in the posted summaries.

Missing-data information is not reported in the registry record. The results include group counts attached to the KOOS outcome, but the record does not describe missing scores, reasons for missingness, imputation, or sensitivity analyses. Without those details, it is not possible to assess whether the posted comparisons could be affected by missing outcome data or how the analysis addressed that possibility.

Other statistical plan details are also not reported in the registry record, including covariate adjustment, any interim analyses, and the handling of protocol deviations. These omissions do not prove that such procedures were absent; they mean their use and implications cannot be established from the record. Interpretation should therefore remain tied to the reported means, standard deviations, mean differences, confidence intervals, and unadjusted p-values.

14. 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 record lists serious adverse events, other adverse events, and deaths by group. For control, it reports 0 serious adverse events among 52 at risk, 0 other adverse events among 52 at risk, and 0 deaths. For autologous bone plus demineralized bone matrix, it reports 0 serious adverse events among 49 at risk, 0 other adverse events among 49 at risk, and 0 deaths. For autologous bone plus calcium phosphate cement, it reports 0 serious adverse events among 47 at risk, 0 other adverse events among 47 at risk, and 0 deaths.

These are the event counts recorded for the listed groups and categories. The registry record provides no serious adverse event terms and reports no event counts in the categories shown. The absence of recorded events in these fields should not be read as proof that no adverse experiences of any kind occurred. The record does not describe the adverse-event collection window, definitions, reporting procedures, or whether all types of events were captured. It also does not provide further safety analyses. Interpretation is therefore limited to the counts as recorded.

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

The posted results show similar numerical mean KOOS scores across the three groups at Month 12 Post-Op: 67.0 for control, 69.0 for autologous bone plus demineralized bone matrix, and 67.7 for autologous bone plus calcium phosphate cement. The pairwise mean differences are 2.0 and 0.7, respectively, and both confidence intervals include zero. The results do not establish a clear difference between either combination group and control on the overall KOOS score.

That interpretation is not the same as concluding that the approaches are equivalent or that they have no effect. The estimates have uncertainty, and the intervals accommodate values on both sides of zero. The record does not report an equivalence margin, a noninferiority margin, or a clinically important difference for KOOS. It therefore does not provide a basis for declaring the approaches equivalent or for deciding whether a possible difference would matter clinically.

The primary measure is a broad patient-reported score covering multiple aspects of knee symptoms and function. Although pain is one of its domains and the trial’s stated concern is anterior knee pain, the posted primary result is not an isolated anterior knee pain outcome. It should not be interpreted as a direct result for that symptom alone.

The record also does not provide detailed information on missing outcomes, analysis populations, participant flow, or the original statistical plan. The absence of these details limits assessment of how complete and robust the posted comparisons are. The reported results describe the score summaries and uncertainty recorded for the comparison, but they do not establish a causal mechanism for any score pattern or support conclusions about outcomes that are not reported.

16. Why This Trial Matters Statistically

This trial addresses a statistical challenge common in clinical research: translating an intervention question into a measurable outcome while preserving the limits of what that outcome represents. The stated concern is anterior knee pain after ACL reconstruction with bone-patellar tendon bone autograft, while the primary measure is the overall KOOS score, which spans pain, symptoms, function, and quality of life. That distinction is important when interpreting what a comparison can answer.

The three-group design provides two direct comparisons of combination fillers with autologous bone control. Reporting means, standard deviations, mean differences, confidence intervals, and p-values allows readers to consider both the estimated direction and the uncertainty. The confidence intervals for both comparisons include zero, so the data do not settle whether either group differs from control on the overall score. Nor do they establish equivalence.

The record illustrates why precision and effect size matter alongside statistical significance. A point estimate is not a complete account of the evidence, and a p-value alone does not describe the range of differences compatible with the data. The planning illustrations also show that the required number of participants per arm depends strongly on the effect selected for detection, under the stated assumptions. Those calculations are not a substitute for the trial’s original design rationale, which is not reported in the registry record.

For readers assessing evidence, the record also highlights the value of clear reporting on missing data, analysis populations, multiplicity, and outcome definitions. Those details are not reported, which constrains interpretation of the statistical results. The posted values still provide a concise account of the recorded primary outcome, but conclusions should remain limited to that outcome and the comparisons available.

17. 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.

Several trial-specific limitations affect interpretation. The record identifies the trial as unmasked, but does not report further details about outcome assessment or the steps used to reduce the influence of unmasked assignment on a patient-reported outcome. The randomization procedure and allocation concealment are also not described in the registry record.

The primary measure is the overall KOOS score, while the stated motivation focuses on anterior knee pain. The record does not report a separate anterior knee pain result or a distinct pain-subcategory result. The outcome therefore does not isolate the symptom named in the trial’s rationale.

The registry record does not explain the group outcome counts in relation to the listed enrollment, provide participant flow, or state how missing scores were handled. It also does not report an analysis population, adjustment for covariates, a multiplicity procedure, or a detailed statistical plan. The listed group means and pairwise comparisons can be interpreted as posted, but these omissions prevent fuller assessment of analysis choices and completeness.

No clinically important difference threshold for KOOS is reported, so the practical importance of the estimated differences cannot be judged from the record alone. The record also does not provide detailed eligibility criteria, baseline group characteristics, adherence information, or longer-term results. These items are not reported in the registry record and should not be inferred from the available outcome summaries.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: The Effect of Bone-void Filler on Anterior Knee Pain Following ACL Reconstruction — NCT04533880.
• Registry record last updated 2024-08-13; status last verified 2024-07.
• Results first posted 2024-08-13.
• 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.

21. Record Summary

NCT04533880 is a completed, randomized, parallel-group trial sponsored by NYU Langone Health. It compares autologous bone from the graft harvest alone with autologous bone combined with demineralized bone matrix or calcium phosphate cement after ACL reconstruction with bone-patellar tendon bone autograft. The registry lists enrollment of 150 and a primary completion date of 2023-07-07.

The primary posted outcome is the overall KOOS score at Month 12 Post-Op, with higher values described as worse. Group means are 67.0 for control, 69.0 for autologous bone plus demineralized bone matrix, and 67.7 for autologous bone plus calcium phosphate cement. Both pairwise confidence intervals include zero. No secondary outcome results are posted, and details about missing data and the trial’s original statistical plan are not reported in the registry record.