Study of CA-008 (Vocacapsaicin) in Total Knee Arthroplasty: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of CA-008 (Vocacapsaicin) in Total Knee Arthroplasty (NCT03731364), a randomized phase 2 study. The primary outcome is Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo.

2. Clinical Question

This is a comparison of average reported pain scores at a specified time, not a comparison of every aspect of recovery or of pain over the entire postoperative period. A lower group mean corresponds to lower average reported pain intensity on this scale, but a mean alone does not describe how scores vary among participants. The standard deviations reported for the groups help convey that variation.

The posted results present three treatment-versus-placebo comparisons, corresponding to the three CA-008 dose cohorts. They do not report a single pooled comparison of all CA-008 cohorts against all placebo participants. The registry record also lists opioid use outcomes among the secondary outcomes, but those results are not part of the primary comparison.

3. Trial Design

The registry identifies this as a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study of CA-008 (vocacapsaicin) in people undergoing elective TKA. It is described as a two-part, multicenter study. The study status is completed, and the recorded enrollment is 55. The sponsor is Concentric Analgesics.

The design included three CA-008 dose cohorts: 5 mg (0.05 mg/mL), 10 mg (0.1 mg/mL), and 15 mg (0.15 mg/mL). Cohort 1 was compared with a separate placebo group. Cohorts 2 and 3 were each compared with the placebo group designated for those cohorts. This structure matters when interpreting the results: the reported analyses are three cohort-specific comparisons, not a single comparison across all doses.

The study record describes quadruple masking. That term indicates a masked design, but the registry record does not report the full operational details of who was masked or how masking was maintained. The placebo descriptions say that the comparator was identical in appearance to the investigational product and contained the same excipients as the active treatment.

The primary efficacy endpoint was designated for the pilot stage and measured time-specific mean pain intensity at 96 hours. The registry identifies the analysis population for that endpoint as the Safety Population. It does not report in the registry record a detailed definition of that population, the handling of participants with missing endpoint measurements, or whether any participants were excluded from the analysis.

The registry record does not report the sample-size justification, the planned statistical analysis details beyond the posted ANOVA comparisons, or whether interim analyses were planned or conducted. The posted results therefore describe the observed group summaries and the reported comparisons, but do not establish the full design rationale or all procedures used in the trial.

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: Safety Population

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: The reason for the difference in the analysis population versus the number of participants in Participant Flow is due to the participant in CA-008 15 mg Cohort 3 who was randomized but not treated with study drug. This participant discontinued early from the study (on the same day of randomization) due to an adverse event.

6. Primary Endpoint

The registry lists the primary outcome as Time-specific Mean Pain Intensity Scores (NRS) at Time 96 Hours for CA-008 vs. Placebo, measured over At 96 hours.

The primary endpoint is the mean pain-intensity score at 96 hours after surgery. Pain intensity was measured on a numerical rating scale ranging from 0, meaning no pain, to 10, meaning the worst pain imaginable. The endpoint is a continuous measure, and the registry reports the mean and standard deviation for each treatment group.

A time-specific score provides a direct summary of participants’ reported pain at a prespecified point in the postoperative course. Using the mean allows the trial to compare average pain scores between a CA-008 cohort and its placebo comparator. The standard deviation adds information about the spread of individual scores around each group mean; it is not the uncertainty interval for the mean or for the between-group difference.

As a general statistical point, patient-reported pain scales can summarize experience in a form suitable for group comparisons, but a group average does not reveal the full distribution of scores or how many participants experienced a particular level of pain. A score at 96 hours also does not, by itself, describe the trajectory of pain at other times. The registry lists the primary endpoint at this single timeframe; other pain timepoints are not specified in the primary endpoint description.

The registry describes this as the primary efficacy endpoint for the pilot stage. It also lists percentage of subjects who do not require opioids and total opioid consumption in daily oral morphine equivalents as secondary outcomes. Those outcomes address related but distinct questions and should not be treated as interchangeable with pain intensity.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the mean summarize?

The primary endpoint is a continuous measure, and the registry reports a mean for each group. In general, the mean is the arithmetic average of the recorded scores and gives a compact summary of the group’s central level. For a bounded rating scale, the mean can be useful for comparing groups, but it does not show whether the observed scores cluster near the average or are spread across the scale.

The standard deviation is a descriptive measure of variability among observations within a group. A larger standard deviation indicates more spread around the mean. It is not a measure of how uncertain the mean is, and it is not a confidence interval for the treatment contrast. The registry lists standard deviations for the five groups but does not report confidence intervals for the group means or between-group effects.

What does ANOVA contribute?

The registry reports ANOVA for each dose-specific superiority comparison. In general, analysis of variance is a model-based method for assessing differences in means. With two groups, an ANOVA comparison evaluates the evidence for a difference in group means under the model’s assumptions. The reported analysis is the sponsor’s analysis as recorded; detailed model specifications, covariate adjustments, and diagnostic checks are not reported in the registry record.

The reported p-values are 0.276 for the 5 mg cohort comparison, 0.651 for the 10 mg cohort comparison, and 0.556 for the 15 mg cohort comparison. A p-value is calculated relative to a null hypothesis and an assumed statistical model. It is not the magnitude of a difference, and it cannot replace an effect estimate with a confidence interval. Since no contrast estimate or confidence interval is reported for these analyses, the reader cannot use the posted p-values alone to determine the range of effects compatible with the data.

How should uncertainty be considered?

In general, a confidence interval gives a range of effect estimates that are reasonably compatible with the data under a specified method. It helps communicate precision, whereas a p-value compresses the evidence into a single measure tied to a null hypothesis. No confidence intervals are reported for the three primary comparisons. The sample counts and standard deviations are available, but they should not be used to imply that a particular recalculated contrast is the sponsor’s result. The registry record does not report a recalculated two-arm comparison.

The spread in scores is relevant because participants’ pain ratings vary. In general, greater variability makes it harder to distinguish a group mean difference from random variation when other features of a study are held constant. A small group can also yield substantial uncertainty even when the observed means differ. These considerations are reasons to look for effect estimates and uncertainty intervals, not a basis for calculating an unreported trial result.

What does masking and randomization address?

Random allocation is intended, in general, to reduce systematic differences in participant characteristics between assigned groups. Masking can reduce the influence of expectations on outcome reporting or assessment. The registry identifies the study as randomized and quadruple-masked. However, details about the allocation sequence, concealment, and the identities of the masked parties are not reported in the registry record. The design label alone cannot establish how well those procedures worked in practice.

The parallel-group structure means participants were assigned to a treatment group rather than crossing between study treatments, as described by the registry’s design classification. The arm descriptions indicate separate placebo comparisons for Cohort 1 and for Cohorts 2 and 3. Accordingly, the three reported tests should be understood as cohort-specific rather than as a single overall dose comparison.

What do planning calculations mean?

In general, sample-size planning asks how many participants would be needed under specified assumptions to detect a chosen effect with a chosen probability, often called power. The planning illustrations associated with these results use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects defined as stated fractions of the observed effect. These are planning assumptions based on an observed effect, not evidence that the trial had a particular level of power.

Such calculations are hypothetical illustrations. They are not observed outcomes, and they do not show that the actual trial was designed around those assumptions. The registry record does not report the trial’s sample-size justification. No planning value should be read as observed power or as a guarantee that a future study would reproduce the same effect.

Why does over-dispersion matter in general?

Over-dispersion is a general concept for data whose variability is greater than a statistical model expects. It can make standard errors too small and p-values too optimistic if the model does not account for the extra variability. The primary endpoint is a continuous pain score, and the registry reports standard deviations, but it does not report an over-dispersion analysis or indicate that over-dispersion was a concern. This concept is therefore methodological context, not a finding about this trial.

What is not specified?

The registry record does not report the detailed statistical analysis plan, the approach to missing endpoint values, any covariate adjustment, whether there were interim analyses, or a multiplicity procedure. It identifies the primary endpoint analysis population as the Safety Population, but does not define that population in detail. These omissions limit assessment of whether the reported analyses followed a prespecified plan and how robust they are to alternative reasonable methods.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("CA-008 5 mg (0.05 mg/mL) Cohort 1", "Placebo - Cohort 1", "CA-008 10 mg (0.1 mg/mL) Cohort 2", "CA-008 15 mg (0.15 mg/mL) Cohort 3", "Placebo - Cohorts 2 and 3")
n   <- c(9, 9, 13, 12, 11)
m   <- c(3.8, 5.1, 4.9, 4.8, 5.5)
sp  <- c(2.11, 2.85, 2.02, 3.47, 2.91)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  CA-008 5 mg (0.05 mg/mL) Cohort 1  9  3.800  2.110  2.178  5.422
CARM  Placebo - Cohort 1  9  5.100  2.850  2.909  7.291
CARM  CA-008 10 mg (0.1 mg/mL) Cohort 2  13  4.900  2.020  3.679  6.121
CARM  CA-008 15 mg (0.15 mg/mL) Cohort 3  12  4.800  3.470  2.595  7.005
CARM  Placebo - Cohorts 2 and 3  11  5.500  2.910  3.545  7.455

11. Analyses Reported by the Sponsor

The registry reports the sponsor’s ANOVA superiority analyses for the three dose-specific comparisons. The reported p-values are 0.276 for CA-008 5 mg versus its placebo comparator, 0.651 for CA-008 10 mg versus its placebo comparator, and 0.556 for CA-008 15 mg versus its placebo comparator. The registry also gives group means and standard deviations at 96 hours.

A recalculated contrast and confidence interval are not reported in the registry record for these comparisons. The posted group summaries should not be mistaken for a sponsor-reported difference estimate. The sponsor’s analysis remains the relevant reported inferential analysis; the record’s discrepancy flag is false, and it does not identify a conflict between sponsor and recalculated results.

Even when a recalculation is available, a simple unadjusted calculation from group summaries may differ from an analysis that uses a model or analysis population specified by the sponsor. Such a recalculation is useful as a check, but it does not supersede the sponsor’s own analysis. In this case, the reported inferential results are the ANOVA p-values, while the uncertainty intervals and detailed model specifications are not reported in the registry record.

The reported p-values should therefore be considered alongside the observed means, the group variability, and the limitations in the record. They do not communicate the size or precision of a treatment contrast by themselves.

12. Multiplicity, Missing Data and Analysis Populations

The posted primary results include three superiority comparisons: each of the three CA-008 dose cohorts is compared with a designated placebo group. When several hypotheses are tested, the chance of at least one apparently unusual result can increase if each test is interpreted separately. In general, a multiplicity plan specifies whether and how inference is adjusted or organized across several comparisons.

The registry record does not report whether a multiplicity adjustment was used, whether the three comparisons were treated as a family, or what testing hierarchy was planned. Consequently, the p-values should be read as the individual reported results, without assuming that they were adjusted or that they share a particular overall error rate. The record also does not report whether other analyses or endpoints were included in a broader testing family.

Missing-data handling is another important part of endpoint analysis. In general, the interpretation of a mean comparison can depend on whether measurements are missing, why they are missing, and how the analysis handles them. The registry record does not report the amount of missing primary endpoint data, the reasons for missingness, or the method used to address missing values. It is therefore not possible to assess from the record whether the analysis used only observed measurements, imputation, or another approach.

The primary endpoint is identified as being analyzed in the Safety Population. The registry does not provide a detailed definition of that population or explain how it relates to randomized participants, treatment received, or endpoint availability. The record also does not report a separate intention-to-treat analysis for this endpoint. Those details matter because different analysis populations can produce different estimates and answer somewhat different questions.

The study is described as having two parts, and the primary endpoint is specified for the pilot stage. The registry record does not report whether the pilot-stage findings influenced later study decisions or whether any formal interim analysis was planned. It also does not give a complete statistical analysis plan. These gaps mean the posted results can be described, but the full confirmatory status and prespecification of the analyses cannot be established from the registry record alone.

13. 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.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: deep vein thrombosis (11.1%), perforated ulcer (9.1%), cerebrovascular accident (8.3%), seizure (8.3%).

The registry lists serious adverse events by treatment group and reports the number affected among the number at risk. For CA-008 5 mg, the figures are 1 of 9; for its placebo group, 0 of 9. For CA-008 10 mg, the reported figures are 0 of 13; for CA-008 15 mg, 1 of 12; and for the placebo group shared by Cohorts 2 and 3, 1 of 11. No deaths are reported in any of these groups.

The serious-event terms listed include Deep vein thrombosis (11.1%), Perforated ulcer (9.1%), Cerebrovascular accident (8.3%), and Seizure (8.3%). The registry record does not report the derivation of these term-specific percentages in the information presented, so they should not be converted into counts or assumed to represent a group-specific risk without further detail.

These are descriptive safety figures from groups with small at-risk counts. They do not establish that an event was caused by study treatment, and they do not provide a stable estimate of event frequency in a broader population. The registry record does not report the timing, duration, relatedness assessment, or full narrative context for these serious events. The numbers should be interpreted as reported event counts, not as a standalone comparative safety analysis.

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

The posted results describe average pain intensity at 96 hours among participants in the listed treatment groups. The CA-008 group means were numerically lower than the corresponding placebo means in all three dose-specific comparisons. The registry also reports the standard deviation for each group and an ANOVA p-value for each comparison. These registry entries characterize the observed endpoint results; they do not alone establish the size, precision, or clinical importance of a treatment effect.

A mean difference, even if numerically apparent in the group summaries, is not enough to judge how precise an effect estimate is. Confidence intervals for the between-group comparisons are not reported in the registry record. The p-values do not supply that missing precision information. The group standard deviations describe variation among scores rather than uncertainty around the treatment effect.

The results do not describe pain over the full recovery period. The primary endpoint is time-specific at 96 hours. Nor do they answer the secondary questions about the percentage of subjects who do not require opioids or total opioid consumption; although those outcomes are listed, their results are not included in the registry record reported for this analysis.

The findings should also be understood within the study’s design and reporting limits. It was a Phase 2 study with several dose-specific comparisons and modest group counts. The registry record does not report the multiplicity procedure, missing-data method, detailed statistical plan, or sample-size justification. These details affect how confidently the observed comparisons can be interpreted.

In general, trial results are most informative when an effect estimate, its uncertainty, outcome definitions, analysis population, and analysis methods can be considered together. The registry provides group summaries and sponsor p-values, but not all of those elements. The posted findings are therefore a record of the measured scores and reported analyses, not proof of a definitive effect or a basis for medical advice.

15. Why This Trial Matters Statistically

This study illustrates why a clinical trial result should be read at the level of its design and analysis, rather than as a single p-value. The endpoint is a patient-reported pain score measured at a specified time, and the results are presented as means and standard deviations for each treatment group. Those summaries answer a clear descriptive question, while the ANOVA p-values address a model-based comparison.

The three-dose structure creates three dose-specific comparisons with separate placebo assignments. That structure makes it important to keep each comparison distinct and to ask how multiple testing was handled. The registry reports the individual analyses but does not report a multiplicity procedure. Without that information, readers should avoid treating the three results as if they came from a single, prespecified overall test.

The record also shows the importance of separating outcome variability from estimation precision. Standard deviations describe the spread of participants’ ratings, while confidence intervals would describe uncertainty in estimated group differences. The registry reports the former but not the latter for the comparisons. A p-value cannot substitute for an effect estimate and interval, particularly when group sizes are modest.

Finally, a completed trial record does not necessarily provide every detail needed to reproduce its analysis. The endpoint population is named, but its definition, missing-data procedures, and fuller statistical plan are not reported. These are not minor technicalities: they shape what population and treatment contrast the results represent. Reading the record carefully helps distinguish what the trial directly reports from what remains uncertain.

16. 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 endpoint is a single time-specific pain assessment at 96 hours. It does not, by itself, describe pain at other times or the pattern of change after surgery. The registry’s primary endpoint description does not provide results at other pain timepoints, and no conclusions about a broader postoperative course can be drawn from this endpoint alone.

The group sizes are limited, with posted counts of 9, 9, 13, 12, and 11. The standard deviations show variability in pain scores, but the registry does not report confidence intervals for the treatment comparisons. Consequently, the precision of the dose-specific effect estimates cannot be evaluated directly from the recorded inferential results.

Three separate dose comparisons are reported, but the registry record does not report a multiplicity plan. It also does not report detailed missing-data handling, the number of missing endpoint values, the full definition of the Safety Population, covariate adjustment, or the full statistical analysis plan. The record does not report the sample-size justification or whether interim analyses were planned or conducted.

The study is described as a two-part Phase 2 trial, and the endpoint is designated as primary for the pilot stage. The record does not explain the relationship between pilot-stage findings and any later study decisions. The available endpoint results therefore cannot establish how the full two-part design was intended to support inference.

The serious adverse-event figures are descriptive and based on small groups. The registry does not report event timing, relatedness, or detailed clinical context in the information summarized. The term-specific percentages are listed, but their derivation is not explained in the registry record. These limitations preclude treating the safety figures as precise comparative risk estimates.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Study of CA-008 (Vocacapsaicin) in Total Knee Arthroplasty — NCT03731364.
• Registry record last updated 2022-02-15; status last verified 2021-12.
• Results first posted 2022-02-15.
• 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.

20. Record Summary

NCT03731364 is a completed, randomized, quadruple-masked, placebo-controlled, parallel-group Phase 2 study of CA-008 (vocacapsaicin) in people undergoing elective TKA. The registry records enrollment of 55 and describes three dose cohorts: 5 mg, 10 mg, and 15 mg, each compared with a designated placebo group.

The primary pilot-stage endpoint was mean pain intensity at 96 hours, measured on a 0–10 numerical rating scale, and analyzed in the Safety Population. The registry reports group means, standard deviations, and ANOVA p-values of 0.276, 0.651, and 0.556 for the three dose-specific comparisons. Confidence intervals for the comparisons are not reported in the registry record.

The registry also lists opioid-related secondary outcomes and serious adverse-event information. The missing-data method, multiplicity approach, detailed statistical plan, and sample-size justification are not reported in the registry record. The posted results describe the recorded endpoint summaries and sponsor analyses, with important limits on precision and interpretation.