Cannabidiol for Bilateral Total Knee Arthroplasty: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cannabidiol for Bilateral Total Knee Arthroplasty (NCT04749628), a randomized phase 4 study. The primary outcome is Cumulative Opioid Usage in First 72 Hours Postoperatively.

2. Clinical Question

The trial’s stated aims extended beyond opioid use. The registry record describes plans to assess whether cannabidiol was associated with minimal opioid use and adequate analgesia, as well as to assess tolerability, pharmacokinetics, and inflammatory markers in the perioperative setting. The primary endpoint addresses opioid consumption, not pain relief itself. Pain at rest and with movement, among other outcomes, appear among the listed secondary outcomes, but results for most of those outcomes are not reported in the registry record.

3. Trial Design

The registry record identifies this as a randomized, controlled, parallel, triple-blind pilot study in patients undergoing bilateral total knee arthroplasty. It lists Phase 4 and a completed status. The recorded start date is 2022-11-02, and the primary completion date is 2024-10-11. The sponsor is Hospital for Special Surgery, New York.

Participants were assigned to Ora-sweet SF, 400mg cannabidiol, or 800mg cannabidiol. The primary endpoint analysis included 12 participants in each group. The record notes that one participant in the Ora-sweet SF group was not included in the analysis because screening failed after enrollment. It does not explain how the randomized allocation was generated, how allocation was concealed, or which people were masked. Those details are not reported in the registry record.

The primary outcome was cumulative opioid use over 0-72 hours postoperatively, expressed in morphine milligram equivalents. The record reports group means and standard deviations, along with comparisons of each cannabidiol group against Ora-sweet SF. The comparisons are unadjusted recalculations from the posted summary statistics; no discrepancy is flagged between those recalculations and the sponsor’s analysis.

The study summary presents the trial as a pilot intended to gather information for future research. The registry record does not report the original sample-size justification or the assumptions used to plan the trial. It lists secondary outcomes covering pharmacokinetics, an inflammatory marker, pain, adverse events, opioid-related symptom distress, and anxiety. Detailed results are available for interleukin-6; results for many other listed outcomes 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: One participant in the Ora-sweet SF group was not included in the analysis due to screen failing after enrollment. Therefore, 12 patients in each group were included in the analysis.

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.

Population: One participant in the Ora-sweet SF group was not included in the baseline characteristics count due to screen failing after enrollment. Therefore, 12 patients in each group were included in the analysis.

6. Primary Endpoint

The registry lists the primary outcome as Cumulative Opioid Usage in First 72 Hours Postoperatively, measured over 0-72 hours postoperatively.

The primary endpoint is cumulative opioid use during the first 72 hours after surgery. It is measured in morphine milligram equivalents (MME), a common scale for expressing opioid use across different opioid medications. The record describes the endpoint as cumulative use over the postoperative period and reports each group’s mean and standard deviation.

This endpoint measures the amount of opioid medication used; it does not directly measure pain intensity or whether pain relief was adequate. Opioid consumption can therefore address one part of the study’s stated question about opioid use, but it needs to be interpreted alongside analgesia and tolerability outcomes to understand the broader clinical picture. Pain at rest and with movement are listed as secondary outcomes, but their results are not reported in the registry record.

As a continuous measure, the mean gives a group-level average, while the standard deviation describes how spread out individual observations are around that average. A mean difference compares the group averages. The primary endpoint comparison is between each cannabidiol group and Ora-sweet SF; the negative estimated differences indicate lower average MME in the cannabidiol group for that comparison. These group summaries do not show the full distribution of individual opioid use.

7. Results Posted in the Registry

• 400mg Cannabidiol: mean 144.00 versus 209.00 on control; difference -65.00 (95% CI -124.92 to -5.08), standardized effect d = -0.87; z-test p = 0.033.
• 800mg Cannabidiol: mean 203.20 versus 209.00 on control; difference -5.80 (95% CI -70.57 to 58.97), standardized effect d = -0.07; z-test p = 0.861.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Levels of Plasma Inflammatory Marker Interleukin-6

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • 400mg Cannabidiol: mean 20.60 versus 12.30 on control; difference 8.30 (95% CI -7.06 to 23.66), standardized effect d = 0.46; z-test p = 0.289.
  • 800mg Cannabidiol: mean 17.70 versus 12.30 on control; difference 5.40 (95% CI -3.32 to 14.12), standardized effect d = 0.51; z-test p = 0.225.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 400mg Cannabidiol and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 800mg Cannabidiol and the control. The interval gives the range of effects that remain compatible with the data.

The registry record lists a range of secondary outcome domains, including cannabidiol pharmacokinetics, plasma interleukin-6, pain at rest and with movement, pain interference, adverse events, opioid-related symptom distress, and anxiety. It reports comparative summary data for interleukin-6. Results for many of the other listed outcomes are not reported in the registry record, so an overall pattern across pain, tolerability, and other secondary measures cannot be assessed from the available results.

The interleukin-6 results add a measure of perioperative inflammation, which addresses a different question from the primary endpoint of cumulative opioid use. They do not directly explain the primary opioid-use comparison, and they should not be treated as evidence that opioid use or analgesia changed. The registry record does not report a joint analysis linking interleukin-6 values to opioid use or pain outcomes.

Secondary outcomes can help characterize a trial, but they generally carry less weight when many outcomes or comparisons are examined without a reported multiplicity strategy. An unadjusted result may appear notable by chance when multiple questions are tested. The registry record does not report a multiplicity adjustment or a hierarchy of secondary hypotheses. It also does not report analyses for most listed secondary outcome domains, limiting the ability to judge whether the primary result aligns with them.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Pharmacokinetics of CBD
• Levels of Plasma Inflammatory Marker Interleukin-6
• NRS Pain at Rest
• NRS Pain With Movement
• Brief Pain Inventory Short Form
• Incidence of Adverse Events
• Opioid Related Symptom Distress Scale (ORSDS)
• Anxiety Levels

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: it records an amount of opioid use rather than a category or event. The registry record reports group means and standard deviations, and the posted comparisons express differences between each cannabidiol group’s mean and the Ora-sweet SF group’s mean. The estimates are unadjusted recalculations from the posted summary statistics. They are not adjusted for other participant characteristics.

What does a mean difference convey?

A mean difference is the difference between two group averages, expressed in the endpoint’s original units. For this endpoint, the unit is MME. A negative estimate means that the cannabidiol group’s average was lower than the comparator group’s average; a positive estimate would mean it was higher. This direction is a description of the comparison, not a conclusion about the clinical importance of the difference.

The standard deviation describes variability among observations within a group. It is not the uncertainty around the group mean; that uncertainty is reflected in the interval around the estimated difference. In general, variability among participants and the number of observations both affect how precisely a group difference can be estimated. The standard deviations reported for the primary endpoint indicate that individual opioid use varied within each analyzed group.

How should the p-values be read?

A p-value measures how unusual the observed data, or data more extreme, would be under a statistical model in which the compared group means are equal. It is not the probability that the groups are equal, and it does not describe the size or importance of a difference. The reported values, 0.033 and 0.861, are unadjusted. They do not incorporate an adjustment for the several outcomes and comparisons in the study. Consequently, the p-values should not be treated as a complete summary of the evidence.

The registry record does not report a sponsor-reported analysis for the primary endpoint among the comparisons listed. The posted estimates are simple unadjusted recalculations from the group summaries, and no discrepancy is flagged. They do not account for any covariate adjustment or other modeling choices that may not be described in the registry record.

Why do the intervals matter?

A confidence interval expresses uncertainty around an estimate under the method used to calculate it. Rather than focusing only on whether a result meets a threshold, readers can use the interval to consider the range of differences compatible with the data and the analysis. An interval that includes zero does not establish that the true difference is zero; it indicates that the data are also compatible with no difference under the interval procedure. An interval excluding zero still leaves uncertainty about the size of the difference.

The interval endpoints for the primary comparisons are reported as -124.9 and -5.082 for 400mg cannabidiol, and -70.57 and 58.97 for 800mg cannabidiol. The latter extends to both negative and positive differences. The width of an interval is informative about precision: broad intervals leave a wider range of possible effects than narrow intervals. The registry record does not state the confidence level or provide a detailed description of the interval method, so those aspects should not be inferred.

What does over-dispersion mean in general?

For count outcomes, over-dispersion means that observed variation exceeds what a simple count model assumes. It can make standard errors too small if the extra variability is ignored. The primary outcome is continuous MME, not a count outcome, so a count-based over-dispersion explanation is not central to interpreting these reported comparisons. More generally, choosing a model that reflects the data’s distribution and variability is important. The registry record does not report a detailed statistical analysis plan or model specification for the primary endpoint.

What can the standardized effect add?

A standardized effect expresses a mean difference relative to a measure of variability, allowing effects measured on different scales to be compared more readily. The posted comparisons include standardized effect estimates, but the endpoint is most directly understood in MME. Standardized estimates do not replace the original-unit mean differences or their intervals, and they do not establish whether an effect is clinically important.

11. Confidence Intervals and Precision

Precision concerns how much uncertainty remains around an estimated group difference. The reported interval for 400mg cannabidiol versus Ora-sweet SF extends from -124.9 to -5.082 MME. It excludes zero, while covering a substantial range of possible negative differences. The point estimate of -65.0 MME is therefore more informative when considered together with the interval than when read alone.

For 800mg cannabidiol versus Ora-sweet SF, the interval extends from -70.57 to 58.97 MME. It includes zero and spans both negative and positive differences. The estimate of -5.8 MME is close to zero, but the interval does not establish that the groups have the same mean; it leaves uncertainty about the direction and size of any difference.

The analyzed groups were small, with 12 participants in each group for the primary outcome. Small groups generally yield less precise estimates when other factors are similar, although precision also depends on variability. The reported standard deviations show variation in opioid use within each group. The interval calculations describe uncertainty under their statistical assumptions, not the range of outcomes for individual participants.

The registry record does not state the confidence level or fully describe the method used to construct these intervals. They should therefore be read as the reported intervals, without assigning an unreported confidence level. Their width and whether they include zero provide useful information, but do not by themselves determine clinical importance.

12. 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 figures are planning illustrations based on the observed effect, not the trial’s original design assumptions. The registry record does not report the original sample-size justification or planning inputs. The illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It considers detecting the stated effect or a fraction of the observed effect.

The figures are participants per arm for 80% power and participants per arm for 90% power. These columns describe planning targets: under the stated assumptions, the power is the chance of detecting an effect of the specified size if that effect is present. The higher power target generally requires more participants for the same effect. The figures are not total sample sizes.

Rows that plan for 100% of the observed effect use the full estimated effect from the posted comparison. Rows planning for 75% or 50% of the observed effect consider smaller effects. Smaller effects are harder to distinguish from random variation, so they require more participants per arm under the same assumptions. The projected sample sizes can therefore change substantially with the effect size used.

The primary comparison estimates come from small groups, so the observed effect used for these illustrations is uncertain. These planning figures are not observed power, and they do not show the probability that the trial’s result is correct. They illustrate how sample-size requirements depend on the assumed effect and the stated planning choices.

13. 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 = -65.000; pooled standard deviation σ = 74.884.
2. n = 2 × (1.96 + 0.842)² × 74.884² / -65.000² = 20.8, rounded up to 21 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 <- -65                      # observed difference in means
sigma <- 74.8838099992248                     # 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(4749628)
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 = 21 (80% power), 28 (90% power)
 75% of observed effect: n per arm = 38 (80% power), 50 (90% power)
 50% of observed effect: n per arm = 84 (80% power), 112 (90% power)
power.t.test: 21.8 
Simulated power at n = 21 per arm: 0.785 (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.

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study examines several outcomes, time points, groups, or statistical comparisons. Each additional test creates another opportunity for an apparently unusual result to arise by chance. The registry record lists multiple secondary outcomes and compares each cannabidiol group with a common comparator for the primary endpoint. The posted primary-comparison p-values are unadjusted, and the record does not report an adjustment for multiple comparisons.

The record does not report a prespecified hierarchy describing which outcomes should be considered primary beyond the named primary endpoint, nor does it describe a procedure for controlling the overall false-positive rate across analyses. The study summary identifies opioid use as a key aim but also describes analgesia, tolerability, pharmacokinetics, and inflammatory markers. Without a reported analysis plan, the intended inferential priority among these questions is not clear. This limits how strongly an isolated unadjusted result can be interpreted.

For the primary endpoint, the record explains that one participant in the Ora-sweet SF group was excluded from the analysis after screening failed following enrollment. The primary analysis included 12 participants in each group. The registry record does not state whether this was an intention-to-treat, per-protocol, or another analysis population, and it does not describe how any other missing primary endpoint data were handled.

For interleukin-6, the reported group sizes are 12 for Ora-sweet SF and 11 in each cannabidiol group. The record does not explain the smaller analyzed groups or report a missing-data method for that outcome. It does not provide sufficient information to determine whether missingness could have influenced the secondary results. The original sample-size assumptions, interim analyses, and detailed statistical plan are not reported in the registry record.

15. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: small bowel obstruction (8.3%), oxygen desaturation (8.3%).

The registry record reports serious adverse events affecting 1 participant in the Ora-sweet SF group, 0 in the 400mg cannabidiol group, and 1 in the 800mg cannabidiol group. Each group had 12 participants at risk for serious adverse events. No deaths are reported. The listed serious event terms are Small Bowel Obstruction and Oxygen Desaturation, each reported as 8.3%; the record does not provide enough detail to assign those terms to a particular group.

Other adverse events affected 4 participants in the Ora-sweet SF group, 3 in the 400mg cannabidiol group, and 5 in the 800mg cannabidiol group; 12 participants were at risk in each group. These are counts of affected participants, not measures of event severity or duration.

These figures are descriptive. With few participants in each group, counts can change noticeably with individual events and cannot precisely characterize uncommon harms. The registry record does not provide detailed event narratives, timing, or a basis for attributing an event to the study intervention. The figures should not be interpreted as establishing comparative safety.

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

The posted primary results show different observed mean opioid-use comparisons for the two cannabidiol groups. Mean cumulative use was lower in the 400mg group than in the Ora-sweet SF group, while the 800mg group mean was close to the comparator mean. The unadjusted estimate for 400mg cannabidiol was -65.0 MME, with an interval from -124.9 to -5.082; for 800mg cannabidiol the estimate was -5.8 MME, with an interval from -70.57 to 58.97. These estimates describe the analyzed participants and their recorded opioid use during the stated postoperative period.

The results do not establish that the observed differences would recur in a larger study, nor do they identify the true magnitude of any difference with precision. In particular, the interval for the 800mg comparison allows both negative and positive differences. Neither comparison alone establishes whether pain relief was adequate, because opioid consumption is not itself a direct measure of analgesia. The registry record does not report results for most listed pain outcomes.

The study is described as a pilot, and the primary endpoint analysis included 12 participants per group. The evidence is therefore limited in its ability to estimate effects precisely or characterize uncommon adverse events. The unadjusted comparisons also need to be interpreted in the context of multiple outcomes and the absence of a reported multiplicity strategy.

These findings are descriptive evidence from one completed randomized trial in patients undergoing bilateral total knee arthroplasty. They do not establish a general result for other patient groups, surgical settings, or cannabidiol regimens. No medical advice or treatment conclusion follows from the posted statistics alone.

17. Why This Trial Matters Statistically

This trial illustrates why an estimated effect should be read together with its uncertainty. The 400mg comparison has a negative point estimate and an interval that excludes zero, while the 800mg comparison has an estimate near zero and an interval that includes values on both sides of zero. Looking only at group means or p-values would miss important information about the range of differences compatible with the data.

It also shows how a pilot study can provide early estimates while leaving substantial uncertainty. With 12 participants analyzed in each primary endpoint group, the observed effects are not precise enough to settle the size of a difference. The sample-size planning illustrations make the dependence on the assumed effect visible: smaller target effects require larger participant counts under the stated assumptions. They are planning aids, not evidence about the probability that this trial’s findings are true.

Finally, the study’s multiple aims make outcome interpretation important. Opioid use, pain, inflammatory markers, and tolerability represent distinct dimensions. A result for one cannot substitute for results on the others. The registry record’s limited reporting of secondary outcome results and lack of a reported multiplicity strategy are relevant when assessing how much weight to place on any single unadjusted comparison.

18. 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 primary analysis is based on small groups, and the registry record reports 12 participants per group. This limits precision and makes the estimated group differences sensitive to variation among individual observations. The trial is identified as a pilot, while the record does not report the original sample-size rationale or its design assumptions.

The primary outcome concerns cumulative opioid use over 0-72 hours. It does not directly measure pain intensity or adequacy of analgesia. Although pain at rest and with movement and other patient-reported outcomes are listed, their results are not reported in the registry record. This leaves the broader relationship between opioid use and analgesia unresolved in the posted results.

The registry record notes an exclusion from the primary analysis after a screening failure following enrollment. It does not specify the analysis population definition or describe a missing-data strategy. For interleukin-6, analyzed group sizes differ from the primary analysis, and the reason and handling are not reported. The detailed randomization, concealment, and masking procedures are also not reported.

Only unadjusted recalculated comparisons are available in the posted results, and no multiplicity adjustment is reported. Secondary results are incomplete, limiting assessment across the trial’s broader aims. The adverse-event counts are descriptive and do not provide detailed information about event timing, duration, or attribution. These limitations constrain conclusions about effect size, consistency across outcomes, and safety.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Cannabidiol for Bilateral Total Knee Arthroplasty — NCT04749628.
• Registry record last updated 2026-05-26; status last verified 2024-10.
• Results first posted 2026-05-26.
• 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.

22. Record Summary

The registry record describes NCT04749628, a completed, randomized, controlled, parallel, triple-blind Phase 4 pilot study of cannabidiol in patients undergoing bilateral total knee arthroplasty. Participants were assigned to Ora-sweet SF, 400mg cannabidiol, or 800mg cannabidiol. The primary endpoint was cumulative opioid use in MME during 0-72 hours postoperatively.

The primary analysis included 12 participants in each group. The mean was 209.0 MME with Ora-sweet SF, 144.0 MME with 400mg cannabidiol, and 203.2 MME with 800mg cannabidiol. The recalculated unadjusted comparisons were -65.0 MME for 400mg and -5.8 MME for 800mg versus Ora-sweet SF. The record also reports interleukin-6 results and adverse-event counts, while results for many listed secondary outcomes are not reported in the registry record.