Pharmacokinetics, Relative Bioavailability and Safety of Xaracoll Implant: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics, Relative Bioavailability and Safety of Xaracoll Implant (NCT02232178), a randomized phase 2 study. The primary outcome is Cmax.

2. Clinical Question

3. Trial Design

The registry identifies this as a Phase 2, randomized, quadruple-masked, parallel-group study. Its official title describes a blinded inpatient investigation of two XaraColl doses—200 and 300 mg bupivacaine HCl—compared with 150 mg bupivacaine HCl infiltration after open laparotomy hernioplasty. The listed interventions correspond to 2 100mg implants, 3 100mg implants, and a 150mg injection.

The study status is completed. The recorded start date is 2014-10-20, and the primary completion date is 2015-02-23. Innocoll is listed as the sponsor. The registry records enrollment as 64. The record does not report details of the randomization procedure, the people covered by quadruple masking, or the method used to maintain masking.

The primary outcome is mean Cmax, in ng/mL, with standard deviation. The timeframe lists repeated sampling at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 72, and 96 hours after surgery. The posted summaries give an outcome count of 26 for the 2 100mg implant group, 24 for the 3 100mg implant group, and 11 for the injection group. The safety summaries list 26, 24, and 12 participants at risk, respectively. The registry record does not explain why the outcome and safety counts differ for the injection group or how the enrollment count relates to these summaries.

The record lists four outcome measures and no posted analysis entries. It does not report the trial’s original sample-size assumptions, detailed analysis populations, missing-data procedures, or a full statistical analysis plan. The planning illustrations discussed elsewhere are based on the observed effects and should not be read as descriptions of the original trial design.

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.

Population: all randomized population

6. Primary Endpoint

The registry lists the primary outcome as Cmax, measured over 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 72, and 96 hours after surgery..

Cmax is the maximum drug plasma concentration. It is used in pharmacokinetic work to describe the highest measured concentration over a specified sampling period. In this study, the primary outcome is reported as a group mean in ng/mL, alongside a standard deviation. The scheduled observations span 0.5 through 96 hours after surgery, so the endpoint concerns the maximum concentration observed across the specified post-surgery measurement period.

As a general statistical point, concentration measures can help characterize how drug levels change after administration. Cmax focuses on the peak rather than the entire concentration-time profile. It does not, on its own, summarize total exposure over time; measures such as area under the concentration-time curve address a different aspect of exposure. Nor does a concentration comparison alone establish a clinical benefit or harm.

The study description says it aimed to assess the pharmacokinetic profile of two implant doses and relative bioavailability compared with local bupivacaine infiltration. The posted primary result is Cmax. The registry record does not report posted secondary outcome results, and the listed Cmax comparisons should not be treated as a complete account of relative bioavailability or of all pharmacokinetic features.

7. Results Posted in the Registry

• 3 100mg Xaracoll Implants: mean 524.80 versus 340.40 on control; difference 184.40 (95% CI 111.91 to 256.89), standardized effect d = 1.43; z-test p = <0.001.
• 150mg Bupivacaine HCl Injection: mean 348.40 versus 340.40 on control; difference 8.00 (95% CI -108.82 to 124.82), standardized effect d = 0.06; z-test p = 0.893.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measure: maximum plasma concentration, in ng/mL. The registry reports its mean and standard deviation for each group. A mean describes the group’s average observed value; a standard deviation describes how spread out the observed values are around that average. The standard deviation is not the uncertainty of the mean. Uncertainty in a mean comparison is reflected more directly by its confidence interval.

The posted group means are 340.4 for 2 100mg XaraColl implants, 524.8 for 3 100mg XaraColl implants, and 348.4 for 150mg bupivacaine HCl injection. The standard deviations are 111.0, 146.4, and 184.0, respectively. The outcome counts are 26, 24, and 11. These summaries give useful descriptive context, but the registry record does not identify the participant-level analysis dataset or explain whether every randomized participant contributed to the endpoint.

The recalculated comparisons express the difference between each comparator mean and the control mean. For the 3 100mg implant group, the recalculated unadjusted mean difference is 184.4 ng/mL, with a 95% confidence interval from 111.9 to 256.9 and p < 0.001. For injection, the recalculated unadjusted mean difference is 8.0 ng/mL, with a 95% confidence interval from -108.8 to 124.8 and p = 0.893. These are unadjusted comparisons of group summaries. The registry record does not report an adjusted model, covariate set, or sponsor analysis method.

A confidence interval describes a range of estimates compatible with the observed data under the assumptions of the calculation. General explanation: if the method’s assumptions are appropriate, a confidence interval gives a way to assess both the direction and precision of an estimated contrast. An interval spanning zero does not establish that the groups are identical. An interval excluding zero is not, by itself, evidence of clinical importance. Interpretation also depends on the outcome’s meaning, the study design, and whether the analysis was prespecified.

A p-value assesses how compatible the observed data are with a null hypothesis under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure effect size. The reported p-values are unadjusted. The registry record does not say whether a multiplicity adjustment was part of the original statistical plan, or whether the p-values correspond to a sponsor analysis. Since no analysis entries are posted, the p-values in these comparisons should be understood as recalculated values rather than a reported sponsor conclusion.

The standardized effect-size values and pooled standard deviations are also part of the recalculated comparison summaries. A standardized effect expresses a mean contrast relative to variability, which can help compare effects measured on different scales. Such a standardized measure does not replace the original-unit mean difference: the latter remains directly interpretable in ng/mL. The registry record does not report a prespecified threshold for a clinically meaningful difference in Cmax.

General statistical principle: variability matters because a mean estimated from highly variable observations is less precise than a mean based on similarly sized data with less variation. Unequal group sizes and unequal variability can also affect the precision of a comparison. The posted group sizes and standard deviations provide context, but the record does not report the full participant-level data or diagnostic checks needed to assess distributional assumptions, influential observations, or model fit.

The outcome is based on repeated scheduled concentration measurements, but the registry’s summary reports only the maximum concentration. The record does not explain how Cmax was derived when a measurement was unavailable, whether the maximum was defined from observed values or through another procedure, or how values outside the scheduled times were handled. These details can matter because the maximum of a series depends on the measurement schedule and data completeness.

The planning illustrations use the observed effect as a starting point and apply the stated assumptions: two-sided significance level 0.05, equal allocation between the two arms, and a normal approximation. The target effect is the stated fraction of the observed effect. For time-to-event outcomes, the stated convention is total events; for all other outcomes, the figures are participants per arm. These assumptions describe the planning illustration only. The trial’s original sample-size justification and assumptions are not reported in the registry record.

For the comparison of 3 100mg implants with control, the planning illustration lists 8 participants per arm for 80% power and 11 for 90% power when planning for 100% of the observed effect; 14 and 19 when planning for 75%; and 31 and 42 when planning for 50%. For injection versus control, the corresponding figures are 4,534 and 6,070 for 100%; 8,060 and 10,790 for 75%; and 18,135 and 24,278 for 50%. These are planning calculations, not estimates of what the completed trial was designed to detect.

As a general concept, over-dispersion occurs when data are more variable than a model assumes. If present, it can make standard errors too small and confidence intervals too narrow unless the analysis accounts for it. The registry record does not report an over-dispersion assessment or a model for the Cmax endpoint, so this concept is relevant as a general caution rather than a claim about this study.

10. Confidence Intervals and Precision

Precision is reflected by the width of the confidence interval as well as the estimated mean difference. The 3 100mg implant comparison has a recalculated mean difference of 184.4 ng/mL, with a 95% confidence interval from 111.9 to 256.9 ng/mL. The interval lies above zero and is narrower than the interval for the injection comparison. It still represents uncertainty about the size of the mean contrast.

For injection versus the 2 100mg implant control, the recalculated mean difference is 8.0 ng/mL, with a 95% confidence interval from -108.8 to 124.8 ng/mL. This interval covers both negative and positive differences, so the estimate is imprecise with respect to the direction and size of the contrast. Its width means that the posted summaries are compatible with a range of possible group differences. It does not establish equivalence or absence of an effect.

The observed outcome counts are 26, 24, and 11 for the 2 100mg implant, 3 100mg implant, and injection groups. The listed standard deviations are 111.0, 146.4, and 184.0 ng/mL. As a general statistical point, smaller analysis groups and greater variability can reduce precision. The combination of group counts and variability is relevant when considering why an interval may be wide, but these summaries do not identify the cause of imprecision or substitute for the original analysis plan.

The record does not report a prespecified precision target, a clinically meaningful Cmax margin, or the original sample-size justification. The confidence intervals are unadjusted recalculations and do not account for any multiplicity procedure that may have been planned. They should be interpreted as estimates of uncertainty around these particular group contrasts, not as certainty about other outcomes or clinical consequences.

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 planning figures are participants per arm, not total events. The event-count convention applies to time-to-event outcomes, while Cmax is a continuous outcome. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and a target effect equal to the stated fraction of the observed effect. These are planning assumptions for the illustration; the trial’s own original design assumptions are not reported in the registry record.

The 80% power column gives the number of participants per arm estimated to yield an 80% chance of detecting the specified effect under those assumptions, if that effect is real and the planning model applies. The 90% power column gives the corresponding number per arm for a higher chance of detection. Greater target power generally requires more participants under otherwise unchanged assumptions.

The rows planning for 100%, 75%, and 50% of the observed effect illustrate how the assumed effect size changes the required sample size. A smaller effect is harder to distinguish from random variation, so planning to detect a smaller effect requires more participants. For example, the recalculated planning figures for the injection comparison are substantially larger than those for the implant comparison, reflecting the very different observed mean contrasts used as the starting point. This does not establish the true effect in a future study.

These figures are not observed power. They are planning illustrations calculated from the observed effects, not a description of the completed trial’s original design or a measure of how likely its findings are to be true. Large calculated requirements for the injection comparison should be read cautiously because the observed contrast is small relative to its variability, and the estimate itself is uncertain.

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 = 184.400; pooled standard deviation σ = 129.228.
2. n = 2 × (1.96 + 0.842)² × 129.228² / 184.400² = 7.7, rounded up to 8 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 <- 184.4                      # observed difference in means
sigma <- 129.22827186804                     # 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(2232178)
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 = 8 (80% power), 11 (90% power)
 75% of observed effect: n per arm = 14 (80% power), 19 (90% power)
 50% of observed effect: n per arm = 31 (80% power), 42 (90% power)
power.t.test: 8.8 
Simulated power at n = 8 per arm: 0.760 (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 registry lists four outcome measures and identifies Cmax as the primary outcome. It reports no posted secondary outcome results and no analysis entries. Details of the other listed outcomes are not included in the available record details. The registry record does not report the full statistical analysis plan, the ordering of secondary analyses, or whether any outcomes were exploratory.

Multiplicity arises when several hypotheses or outcomes are tested. As a general statistical principle, testing more hypotheses without an appropriate strategy can increase the chance of at least one apparently unusual result arising by chance. The posted Cmax comparisons have unadjusted p-values. Whether the original analysis adjusted for multiple comparisons, and what family of tests would have been covered, are not reported in the registry record. No adjusted inference should be assumed from the available summaries.

Information about missing data is also limited. The record does not describe the number or reasons for missing concentration measurements, how missing values were handled, or how a participant with incomplete scheduled samples could contribute to the Cmax calculation. It does not report sensitivity analyses for missing data. The primary outcome group counts are 26, 24, and 11, while the listed enrollment is 64; the registry record does not explain the relationship between these figures. For safety, the injection group has 12 participants listed at risk, compared with an outcome count of 11. The reason for that difference is not reported.

The record does not define an intention-to-treat, per-protocol, or other analysis population, nor does it say how participants were classified for analysis after randomization. Randomization is recorded, but the allocation procedure and any post-randomization exclusions are not described in the available record. These missing details limit assessment of whether the posted summaries represent all randomized participants and how departures from the intended study procedures may have been handled.

14. 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 non-serious adverse event terms

The serious adverse event summaries list 0 affected participants in each group: the 2 100mg implant group had 0 among 26 at risk, the 3 100mg implant group had 0 among 24 at risk, and the injection group had 0 among 12 at risk. The registry lists no serious adverse event terms. These are counts in the posted safety summaries; they do not establish that no serious events occurred outside the recorded groups or reporting period.

The registry record does not report death counts; those entries are not reported in the registry record. It also does not provide definitions or event-level details for the category of other adverse events. The listed numbers affected by other adverse events are 21, 15, and 8 in the respective groups, with corresponding at-risk counts of 26, 24, and 12. These counts should not be treated as severity-specific, causal, or comparative risk estimates without further definitions and analysis.

Safety summaries use an injection-group at-risk count of 12, whereas the posted Cmax summary gives an outcome count of 11 for that group. The registry record does not explain this difference. The absence of a reported serious event in these summaries does not establish comparative safety.

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

The posted results describe mean Cmax after open laparotomy hernioplasty. The 3 100mg implant group has a higher mean Cmax than the 2 100mg implant control in the recalculated unadjusted comparison, with a confidence interval that lies above zero and p < 0.001. The injection group’s mean is close to the control mean in the descriptive summaries, but its recalculated confidence interval is wide and includes zero.

Those statements concern only the measured maximum plasma concentration and the specified comparisons. They do not show how the groups compare on every part of the concentration-time profile, because Cmax does not summarize total exposure. They also do not establish clinical efficacy, duration of analgesia, or a patient-centered benefit. The registry record does not report posted secondary outcome results that would address such questions.

The injection comparison’s interval is not a demonstration of equivalence. Equivalence requires a prespecified acceptable range for differences and an analysis designed to test that question. Neither is reported in the registry record. Similarly, a statistically distinguishable Cmax mean does not by itself establish that the difference is clinically important.

The safety counts report no serious adverse events among those listed at risk, but the record does not report deaths and gives limited detail on other adverse events. These summaries are not sufficient to establish that one intervention is safer than another. The trial’s completed status and randomized design describe the study, but do not resolve the limitations in the posted outcome, analysis, and missing-data information.

Overall, the available statistics support a descriptive and unadjusted interpretation of the Cmax comparisons. They do not provide a complete account of the trial’s planned inferential analysis or the broader clinical questions raised by the study objectives. The registry record does not report the sponsor’s inferential analysis, multiplicity handling, or original sample-size rationale.

16. Why This Trial Matters Statistically

This trial raises a useful statistical distinction between a pharmacokinetic endpoint and a clinical outcome. Cmax measures the peak concentration observed over the scheduled sampling period. A difference in that measure describes concentration profiles at their peak; it does not automatically answer questions about total drug exposure, patient experience, or clinical benefit. Making that distinction helps keep interpretation aligned with the endpoint actually reported.

The three group summaries also illustrate why estimates need both a point estimate and a measure of precision. The recalculated implant-dose contrast is estimated more clearly than the injection contrast, whose confidence interval spans a wide range of possible differences. A p-value alone would not communicate that uncertainty or the scale of the contrast in ng/mL. Reading the mean difference and confidence interval together gives a fuller view of what the posted summaries can support.

The study also highlights the importance of transparent reporting. The registry lists an enrollment of 64, outcome counts that differ across groups, and an injection safety at-risk count that differs from its outcome count. The reasons are not reported in the registry record. Likewise, no analysis entries, secondary outcome results, or original design assumptions are reported. These omissions make it harder to evaluate analysis populations, missing data, multiplicity, and the relationship between the trial’s planned and posted analyses.

Finally, observed-effect-based planning illustrations can be educational but should not be confused with the trial’s design justification. The figures vary substantially with the effect size chosen for planning, and the smallest assumed effects require more participants. This reinforces that sample-size planning depends on a prespecified target and assumptions, rather than simply restating an observed result.

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.

The posted Cmax results are group summaries rather than participant-level data. The registry record does not report the detailed method used to derive each participant’s maximum concentration, how incomplete sampling was handled, or the distribution of values within groups. It is therefore not possible to assess outliers, distributional shape, or the influence of individual observations from these summaries alone.

The record lists enrollment as 64, but the Cmax outcome counts are 26, 24, and 11. Safety at-risk counts are 26, 24, and 12. No explanation is reported for these counts, and no analysis populations or post-randomization exclusions are described. This limits assessment of how complete the endpoint data were and whether the posted groups correspond to all randomized participants.

The recalculated comparisons are unadjusted. The registry record contains no analysis entries and does not report an analysis plan, adjustment for multiplicity, or a sponsor-reported inferential result. The confidence intervals and p-values therefore do not resolve how the trial’s planned statistical analysis treated multiple outcomes or comparisons. Original sample-size assumptions and the rationale for enrollment are also not reported.

The primary endpoint is one pharmacokinetic summary, Cmax, measured at scheduled times after surgery. The registry record does not provide posted secondary results, and the Cmax findings cannot answer broader questions about total exposure, clinical outcomes, or comparative safety. Safety reporting is limited: no serious adverse events are listed, death counts are not reported in the registry record, and details for other adverse events are not described. These limitations should be considered when interpreting the available summaries.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Pharmacokinetics, Relative Bioavailability and Safety of Xaracoll Implant — NCT02232178.
• Registry record last updated 2020-10-20; status last verified 2020-09.
• Results first posted 2018-08-23.
• 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

The registry identifies NCT02232178 as a completed Phase 2 randomized, quadruple-masked, parallel-group inpatient study sponsored by Innocoll. It examined 2 100mg XaraColl implants, 3 100mg XaraColl implants, and 150mg bupivacaine HCl injection after open laparotomy hernioplasty. Enrollment is recorded as 64; the study start date is 2014-10-20, and primary completion is recorded as 2015-02-23.

The primary outcome is mean Cmax in ng/mL, with standard deviation, measured from 0.5 through 96 hours after surgery at the listed timepoints. The posted group means are 340.4, 524.8, and 348.4, respectively. The registry record lists four outcome measures but no posted secondary outcome results and no analysis entries. It does not report the original sample-size assumptions, detailed analysis populations, or missing-data procedures.