Minimally Invasive Thoracic Surgery Intercostal Nerve Block Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Minimally Invasive Thoracic Surgery Intercostal Nerve Block Trial (NCT03508830), a randomized phase 3 study. The primary outcome is Average Daily In-Hospital Use of Opioids.

2. Clinical Question

In plain terms, the trial asks whether the choice of local anesthetic for the block is associated with a difference in opioid use during the hospital stay after minimally invasive lung resection. The registry also records average daily in-hospital pain score, postoperative pneumonia and length of stay as secondary outcomes. These outcomes provide additional descriptions of recovery and hospitalization, but they are not substitutes for the primary outcome and should not be treated as independent confirmation of it.

The primary endpoint is an average over each participant’s hospitalization, which the registry describes as up to one week. The clinical question is therefore about average opioid use per day during the observed inpatient period, not total opioid use after discharge or long-term pain. Follow-up beyond the specified inpatient period is not reported in the registry record.

3. Trial Design

The Minimally Invasive Thoracic Surgery Intercostal Nerve Block Trial is registered as a phase 3, randomized, parallel-group trial with an active comparator. The registry describes it as single-center and states that it compares liposomal bupivacaine with standard bupivacaine for intercostal nerve block in people undergoing robotic or video-assisted thoracoscopic lung resection. The recorded enrollment is 91, and the trial status is completed.

The registry’s brief summary calls the trial double-blind, while the design fields record triple masking. The registry record does not explain which participants, clinicians or other personnel were masked, or why the two descriptions differ. Allocation is listed as randomized. Details of the sequence-generation method, allocation concealment and any procedures used to maintain masking are not reported in the registry record.

Both arms received an active drug intervention. The arm descriptions identify the block as involving injections into intercostal spaces and surgical wounds at the conclusion of surgery. The registry gives preparation details, but its displayed descriptions are incomplete, so a complete account of the formulations cannot be reconstructed from the record alone.

For the primary outcome, results are posted for 41 participants in the liposomal bupivacaine arm and 39 in the standard bupivacaine arm. These are the arm counts accompanying the outcome summaries; they are not the same information as the overall recorded enrollment. The registry does not explain the relationship between the recorded enrollment and the outcome-specific counts, nor does it report a participant flow account or reasons for any missing outcome data.

The recorded start date is 2018-12-30 and the primary completion date is 2021-01-30. The original protocol, the trial’s prespecified statistical analysis plan and details of any interim monitoring are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

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 Average Daily In-Hospital Use of Opioids, measured over Average over Entire Length of Hospitalization (Up to 1 Week).

The primary endpoint is average daily in-hospital use of opioids, expressed in oral morphine equivalents per day. The registry describes the measure as the average over the entire length of hospitalization, up to one week. The posted summary reports the mean and standard deviation for each treatment arm.

As a general statistical concept, converting opioid medications to a common morphine-equivalent scale allows use across different opioid drugs to be summarized using a shared unit. An average per day describes the typical daily amount over the measured inpatient period; it is not the same as a cumulative total, an assessment of pain intensity, or opioid use after discharge. The registry does not provide further detail on how medication records were collected or converted to oral morphine equivalents.

The endpoint was selected to address the trial’s stated question about analgesic efficacy and opioid use after surgery. In general, opioid use can reflect pain management and clinical practice as well as patients’ pain experiences, so it should be interpreted alongside other relevant outcomes rather than as a direct measure of pain alone. The registry separately lists average daily in-hospital pain score as a secondary outcome. The endpoint’s specified timeframe limits the inference to the hospitalization period recorded in the registry.

7. Results Posted in the Registry

• Liposomal Bupivacaine: mean 40.00 versus 45.00 on control; difference -5.00 (95% CI -17.05 to 7.05), standardized effect d = -0.18; z-test p = 0.416.

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.

Average Daily In-Hospital Pain Score

• 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:
  • Liposomal Bupivacaine: mean 2.70 versus 3.10 on control; difference -0.40 (95% CI -1.15 to 0.35), standardized effect d = -0.24; z-test p = 0.293.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Liposomal Bupivacaine and the control. The interval gives the range of effects that remain compatible with the data.

Number of Participants With Postoperative Pneumonia

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Liposomal Bupivacaine: 0.0% (0/41) versus 2.6% (1/39) on control; risk difference -2.6 percentage points (95% CI -7.5 to 2.4); unadjusted two-proportion z-test p = 0.302.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Liposomal Bupivacaine and the control. The interval gives the range of effects that remain compatible with the data.

Length of Stay

• 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:
  • Liposomal Bupivacaine: mean 2.20 versus 2.30 on control; difference -0.10 (95% CI -0.63 to 0.43), standardized effect d = -0.08; z-test p = 0.711.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Liposomal Bupivacaine and the control. The interval gives the range of effects that remain compatible with the data.

Across the secondary outcomes, the numerical mean differences for pain score and length of stay are in the direction of lower observed averages in the liposomal group. The pneumonia count differs in the opposite arm-level pattern, with the single posted event in the standard bupivacaine group. This broad pattern does not amount to consistent evidence of a treatment effect: the secondary comparisons are uncertain, and their intervals include no difference.

The secondary outcomes relate to the primary question by describing pain and aspects of the inpatient course alongside opioid use. They do not measure the same construct. A pain score is a direct recorded pain measure, pneumonia is an event count, and length of stay describes the duration of the hospitalization. A pattern across these measures may provide context, but it cannot be treated as a substitute for the primary opioid-use comparison or as proof that the primary finding has been confirmed.

Unadjusted secondary results carry less weight when several outcomes are examined because, as a general statistical issue, multiple comparisons increase the opportunity for chance findings. The registry does not report a multiplicity plan, a hierarchy among secondary endpoints or confirmatory testing procedures. The secondary results should therefore be regarded as descriptive evidence whose interpretation is limited by uncertainty and by the absence of a reported approach to multiplicity.

The registry lists three secondary outcomes and reports no analyses for them. The posted group summaries and unadjusted comparisons are useful for describing the observed results, but the record does not establish that these were prespecified analyses or that all planned outcomes have been posted. The relationship between these secondary findings and any broader clinical conclusions remains limited to the endpoints and inpatient timeframe recorded.

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

• Average Daily In-Hospital Pain Score
• Number of Participants With Postoperative Pneumonia
• Length of Stay

9. Statistical Interpretation

10. Statistical Methods Explained

What does a mean difference represent?

For a continuous outcome, a mean difference subtracts the comparator-group mean from the intervention-group mean. Here, the comparison is liposomal bupivacaine minus standard bupivacaine. A negative value therefore means the observed average was lower in the liposomal group; a positive value would mean it was higher. This direction is a description of the statistic, not a judgment about clinical importance.

The primary outcome is reported as a mean with a standard deviation for each arm. A mean summarizes the central level of the measured outcome, while a standard deviation describes how dispersed individual observations are around that mean. These summaries do not show the shape of the underlying distributions, possible outliers or the distribution of individual treatment responses. Those details are not reported in the registry record.

How should the confidence interval be read?

A confidence interval gives a range of values compatible with the observed data and the statistical procedure used to form the interval. In general, a wider interval means less precision, while a narrower interval means greater precision. The primary interval extends from -17.05 to 7.052 oral morphine equivalents per day for the mean difference. Because it spans zero, it does not exclude no difference between the group means. It also includes differences in both directions, so the point estimate alone does not capture the uncertainty.

Confidence intervals are not guarantees that the true effect lies inside a particular interval, nor do they describe the range of individual participants’ outcomes. They address uncertainty about a group-level comparison under the assumptions of the method. The registry does not report the specific interval-construction procedure or any model adjustments for the primary outcome.

What does the p-value add?

The primary unadjusted p-value is 0.416. In general, a p-value describes how unusual data at least as discordant with a specified no-difference model would be, if that model and the analysis assumptions were correct. It is not the probability that the no-difference model is true, and it does not measure the size or clinical importance of a difference. It should be considered with the estimated mean difference and its confidence interval, not in isolation.

The registry has no reported analyses for the primary outcome, and the displayed comparison is an unadjusted summary-statistic comparison. Adjustment variables, if any, are not reported in the registry record. No discrepancy is flagged between the posted group summaries and the comparison values. A prespecified analysis plan and the trial’s original analysis assumptions are not reported in the registry record.

Why does variation matter?

General statistical principle: greater variation among participants makes it harder to estimate a group difference precisely when the amount of data is fixed. The primary group standard deviations are 28.0 and 27.0, compared with a mean difference of -5.0. The uncertainty in the comparison is reflected in its confidence interval. A standard deviation and a confidence interval have different meanings: the former describes outcome spread among participants, while the latter describes uncertainty about the estimated group contrast.

General statistical principle: over-dispersion occurs when observed variability exceeds what a particular statistical model assumes. When that happens, standard errors and tests based on the model can be too optimistic unless the analysis accounts for the extra variation. The registry reports means and standard deviations for this continuous endpoint but does not report an over-dispersion assessment or a model-specific diagnostic. There is therefore no basis in the record to say that over-dispersion was present or that a particular correction was used.

What can the secondary comparisons tell us?

The secondary continuous outcomes are also presented as group means and standard deviations. Their mean differences and intervals can be read using the same general principles: the sign indicates which group’s observed mean is lower, and an interval crossing zero does not rule out no difference under the stated comparison. Postoperative pneumonia is a count outcome, and its posted comparison is a risk difference. In general, a risk difference describes the difference between the proportions with an event in the two groups. The registry does not report adjusted analyses for these secondary outcomes.

These statistical explanations describe general concepts, not an unreported protocol. The registry does not state a distributional model, transformation, covariate set, missing-data procedure or analysis-population definition for the posted outcomes. As a result, the summaries support descriptive comparisons, but the precise analysis procedures beyond those stated in the record cannot be reconstructed.

11. Confidence Intervals and Precision

The primary mean difference is -5.0 oral morphine equivalents per day, with a 95% confidence interval from -17.05 to 7.052. The interval crosses zero, so the posted data are compatible with no difference as well as differences favoring either direction in the numerical comparison. Its breadth shows that the estimate is not precise enough to distinguish a modest difference from a larger one in either direction.

Precision is separate from whether an estimate is clinically important. The registry does not report a threshold for a meaningful change in opioid use, so the interval cannot be classified against a trial-defined clinically important difference. Nor does the interval establish equivalence: that would require an explicit equivalence margin and a design and analysis aimed at testing it, which are not reported in the registry record.

General statistical concept: confidence intervals represent uncertainty in an estimate, not the range of outcomes expected for individual participants. The observed standard deviations describe outcome variability within the groups, while the confidence interval describes uncertainty around the estimated group difference. Both help characterize the evidence, but they answer different questions.

The pain score and length-of-stay intervals also include zero, and the pneumonia risk-difference interval spans zero. These intervals likewise do not identify a clear separation in the posted unadjusted comparisons. Their precision should be considered in context: the outcome-specific group counts are limited, and the registry does not report a prespecified precision target or a multiplicity adjustment. The record does not provide enough information to distinguish whether uncertainty reflects the observed variability, sample size, analysis choices or other factors.

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 planning figures are participants per arm for the continuous outcomes, not total participants across both arms. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms and a normal approximation. The effect used for planning is the stated fraction of the observed effect. The registry does not report the trial’s original sample-size assumptions or justification.

The 80% power column describes the planned number of participants per arm that would yield an 80% chance of detecting the specified effect under those planning assumptions, if that effect and the assumptions were correct. The 90% power column uses a higher target chance of detecting the same specified effect, and therefore gives a larger planned number. These are planning illustrations based on the observed effect, not the original design calculation for this trial.

For the primary outcome, the entries are 476 participants per arm for 80% power and 637 for 90% power when planning for 100% of the observed effect. For 75% of the observed effect, the corresponding entries are 846 and 1,132; for 50% of the observed effect, they are 1,902 and 2,547. Smaller effects require more participants to detect under the same assumptions, because a smaller separation is harder to distinguish from random variation.

These figures are not observed power. They are not evidence that the completed trial had a particular probability of success, and they do not change the interpretation of the observed estimate or confidence interval. A separate planning illustration is also available for each continuous secondary outcome. For a time-to-event endpoint, the stated convention would be total events, but the outcomes in this trial are not presented as time-to-event measures.

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 = -5.000; pooled standard deviation σ = 27.517.
2. n = 2 × (1.96 + 0.842)² × 27.517² / -5.000² = 475.5, rounded up to 476 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 <- -5                      # observed difference in means
sigma <- 27.5173604876109                     # 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(3508830)
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 = 476 (80% power), 637 (90% power)
 75% of observed effect: n per arm = 846 (80% power), 1,132 (90% power)
 50% of observed effect: n per arm = 1,902 (80% power), 2,547 (90% power)
power.t.test: 476.4 
Simulated power at n = 476 per arm: 0.800 (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

The registry lists a primary outcome and three secondary outcomes, but it does not report how the statistical testing plan addressed multiple outcomes. No multiplicity adjustment, testing hierarchy or rule for interpreting secondary findings is reported in the registry record. Without such information, unadjusted secondary p-values should not be treated as if they provide independent confirmatory tests. The record also does not report whether any outcomes were exploratory or how the primary endpoint was prioritized in the formal analysis plan.

The registry does not report a missing-data procedure for the primary or secondary outcomes. It does not describe whether outcome summaries include all randomized participants, how incomplete hospital records were handled, whether any imputation was used, or whether sensitivity analyses assessed the influence of missing observations. The outcome summaries give arm-specific counts, but those counts alone do not explain why the primary outcome counts differ from the overall recorded enrollment.

Analysis populations are also not defined in the registry record. It is not stated whether results follow an intention-to-treat, per-protocol or other population, nor whether participants were analyzed according to randomized assignment. These distinctions can affect interpretation, especially when the analysis counts do not include every enrolled participant.

The registry records no reported analyses for the primary outcome and no reported analyses for the secondary outcomes. It also does not describe interim analyses, stopping rules, covariate adjustment or the complete statistical analysis plan. The posted means, standard deviations, comparisons and intervals provide information about the observed summaries, but they do not fill these gaps about how the trial was planned or conducted. Any interpretation of inferential results should therefore remain within the limits of the information recorded.

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 0% reporting threshold.

The registry records zero serious adverse events and zero other adverse events in the liposomal bupivacaine group, with 41 participants at risk for each category. It records zero serious adverse events and zero other adverse events in the standard bupivacaine group, with 39 participants at risk for each category. Deaths are recorded as zero in both groups.

These entries describe the adverse-event counts posted in the registry; they do not establish that no adverse events of any kind occurred during the trial. The record’s serious-event term list is empty, and no further event descriptions are provided. The registry does not report the event definitions, collection procedures, observation period for adverse events or whether any events were judged related to treatment.

Zero recorded events in these groups should be interpreted in light of the number of participants and the information available in the registry. They cannot rule out uncommon events or provide a comprehensive comparison of safety. The posted figures are a record of reported counts, not a basis for individual medical decisions or a complete assessment of risks.

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

The results show that the observed average daily opioid use was lower in the liposomal bupivacaine group than in the standard bupivacaine group. The estimated mean difference is -5.0 oral morphine equivalents per day, but its confidence interval crosses zero and spans values in both directions. The data therefore do not provide a precise estimate that clearly separates the groups on the primary outcome.

This does not show that the treatments are equivalent, and it does not establish that either treatment is superior. Failure to identify a clear difference is not the same as proof of no difference. An equivalence or non-inferiority conclusion would require a defined margin and an analysis designed for that purpose; neither is reported in the registry record.

The secondary outcomes provide additional descriptions of inpatient pain, pneumonia and length of stay, but they are also uncertain and their testing is unadjusted. They should not be used to override the primary result or to imply a broader conclusion about analgesia or recovery. The adverse-event entries record no serious or other events and no deaths in either group, but this limited record cannot rule out events that were not recorded or uncommon risks.

The findings apply to the randomized trial population and the inpatient setting described in the registry: people undergoing lung resection with robotic or video-assisted thoracoscopic surgery at a single center. The record does not establish how results would generalize to other operations, institutions or timeframes. It also does not provide follow-up outcomes after discharge.

Overall, the registry supports a cautious reading of the observed group summaries and their uncertainty. It does not support a definitive claim about treatment efficacy, equivalence, or overall safety.

17. Why This Trial Matters Statistically

This trial offers a useful example of why a point estimate should be read together with its uncertainty. The primary mean difference is negative, but the interval includes zero and extends in both directions. Reporting the direction alone would conceal the limited precision of the comparison; relying on a p-value alone would likewise omit the size and range of compatible effects.

The endpoint also illustrates the distinction between opioid use and pain. Opioid consumption is a clinically relevant measure of inpatient care, but it is not identical to a pain score. The separate pain outcome can add context, while remaining a secondary measure with its own uncertainty. Interpreting several outcomes together requires attention to their different meanings and to the fact that no multiplicity strategy is reported.

From a planning perspective, the sample-size illustrations show how strongly the required participant count depends on the effect size chosen for detection. Smaller target effects require larger planned groups under the stated assumptions. Because these illustrations use the observed effect rather than the trial’s original design assumptions, they should not be mistaken for a retrospective judgment about the trial’s design or its probability of finding a result.

Finally, the registry’s incomplete reporting of analysis populations, missing data, masking roles and statistical plans limits the ability to reproduce or fully evaluate the analysis. Recognizing those limits is part of statistical interpretation: posted summaries can inform readers while still leaving important design and analysis questions unanswered.

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 registry describes a single-center trial, so the results may not represent outcomes in other institutions or surgical settings. The population is defined by lung resection using robotic or video-assisted thoracoscopic surgery; the record does not establish applicability to other procedures. The recorded enrollment is 91, while primary outcome summaries list 41 participants in the liposomal group and 39 in the standard group. A participant flow description and an explanation of the outcome counts are not reported in the registry record.

The primary comparison has considerable uncertainty, with a confidence interval that includes zero and values in both directions. The registry does not state a clinically important difference, so the practical meaning of the estimated difference cannot be assessed against a trial-defined threshold. The reported comparison is unadjusted, and no analysis population or missing-data method is described.

There are reporting gaps relevant to bias and reproducibility. The summary describes double-blinding while the design field lists triple masking, but masking roles and implementation are not reported. Details of randomization and allocation concealment are also not reported in the registry record. The posted arm descriptions do not provide complete formulation details.

The registry does not report the original sample-size justification, analysis plan, multiplicity approach, interim analyses or results beyond the stated inpatient outcomes. Adverse-event reporting is limited to the posted counts and does not include further definitions or event descriptions. These limitations restrict conclusions about precision, generalizability, analysis choices and safety.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Minimally Invasive Thoracic Surgery Intercostal Nerve Block Trial — NCT03508830.
• Registry record last updated 2021-06-08; status last verified 2021-05.
• Results first posted 2021-06-08.
• 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

NCT03508830 is a completed phase 3 randomized, parallel-group, active-comparator trial of liposomal bupivacaine versus standard bupivacaine for intercostal nerve block during minimally invasive lung resection. The registry describes a single-center study and records enrollment of 91.

The primary outcome is average daily in-hospital opioid use in oral morphine equivalents per day. The posted group means are 40.0 for liposomal bupivacaine and 45.0 for standard bupivacaine. The estimated mean difference is -5.0, with a 95% confidence interval from -17.05 to 7.052 and an unadjusted p-value of 0.416. The interval includes no difference and remains compatible with effects in either direction.

Secondary outcomes include average daily pain score, postoperative pneumonia and length of stay. The record does not report a multiplicity strategy, missing-data procedure, analysis population or complete statistical plan. Results should be interpreted as posted summaries with these reporting limitations in mind.