Optimal Dose of Combination of Rocuronium and Cisatracurium: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Optimal Dose of Combination of Rocuronium and Cisatracurium (NCT02495038), a randomized na study. The primary outcome is Onset of Neuromuscular Blocking Agents(NMBAs).

2. Clinical Question

3. Trial Design

This was a randomized, quadruple-masked, parallel-group trial sponsored by Yonsei University. The registry record lists an enrollment of 81 and a completed status. Participants were allocated to the intubating-dose group, the 10% reduction group or the 20% reduction group, with 27 participants in each group. The registry record does not describe the randomization sequence or how masking was maintained for participants, clinical staff, outcome assessors or analysts.

The trial summary describes preparation of the study drugs by a nurse who was not involved in the study. It says that the drugs were administered and a timer started alongside neuromuscular monitoring. The trial used train-of-four monitoring of the ulnar nerve, with stimulation at 2 Hz per 12 sec. The summary describes total intravenous anesthesia and use of a one-way ANOVA, with α=0.05 and β=0.2.

The primary outcome was the mean onset time, in seconds, from initial administration of neuromuscular blocking agents to a train-of-four ratio of zero. Secondary outcomes listed in the record were operation time, anesthetic time and additional rescue doses per hour. The registry record does not describe the sample-size justification for the original trial, the planned analysis populations, or the intended handling of missing data. The trial dates are recorded as a start in 2014-03 and primary completion in 2015-02.

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

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 Onset of Neuromuscular Blocking Agents(NMBAs), measured over Intraoperative, an average of 5 minutes.

The primary endpoint is onset time: the interval from administration of the initial neuromuscular blocking agents to a train-of-four ratio of zero. It is recorded in seconds and summarized as a mean with a standard deviation. The registry describes assessment during general anesthesia, up to 15 minutes, and gives the timeframe as intraoperative, an average of 5 minutes.

Train-of-four monitoring applies repeated stimulation to a peripheral nerve and measures the resulting muscle response. In this trial, the ulnar nerve was stimulated, and the recorded endpoint marks the point at which the train-of-four ratio reached zero. The endpoint therefore captures the timing of a monitored neuromuscular response after administration; it is not a direct measure of patient experience or a broad measure of surgical outcome.

Comparing mean onset times across the three dose groups addresses whether the observed timing differed with the tested dose combinations. The standard deviation describes variation in onset times among participants in each group. Interpretation should consider both the size of the estimated difference and its uncertainty, as well as the specific monitoring and anesthesia conditions described in the record.

7. Results Posted in the Registry

• 10% Reduction of Combination of Esmeron® and Nimbex®, Group S: mean 230.10 versus 212.80 on control; difference 17.30 (95% CI -13.82 to 48.42), standardized effect d = 0.30; z-test p = 0.276.
• 20% Reduction of Combination of Esmeron® and Nimbex®, Group L: mean 399.30 versus 212.80 on control; difference 186.50 (95% CI 126.88 to 246.12), standardized effect d = 1.67; z-test p = <0.001.

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.

Operation Time

• 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:
  • 10% Reduction of Combination of Esmeron® and Nimbex®, Group S: mean 147.00 versus 151.80 on control; difference -4.80 (95% CI -20.47 to 10.87), standardized effect d = -0.16; z-test p = 0.548.
  • 20% Reduction of Combination of Esmeron® and Nimbex®, Group L: mean 145.90 versus 151.80 on control; difference -5.90 (95% CI -20.52 to 8.72), standardized effect d = -0.22; z-test p = 0.429.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 10% Reduction of Combination of Esmeron® and Nimbex®, Group S 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 20% Reduction of Combination of Esmeron® and Nimbex®, Group L and the control. The interval gives the range of effects that remain compatible with the data.

Anesthetic Time

• 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:
  • 10% Reduction of Combination of Esmeron® and Nimbex®, Group S: mean 159.90 versus 163.00 on control; difference -3.10 (95% CI -18.44 to 12.24), standardized effect d = -0.11; z-test p = 0.692.
  • 20% Reduction of Combination of Esmeron® and Nimbex®, Group L: mean 161.40 versus 163.00 on control; difference -1.60 (95% CI -15.66 to 12.46), standardized effect d = -0.06; z-test p = 0.823.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 10% Reduction of Combination of Esmeron® and Nimbex®, Group S 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 20% Reduction of Combination of Esmeron® and Nimbex®, Group L and the control. The interval gives the range of effects that remain compatible with the data.

Additional Rescue Doses Per Hour Ratio.

• 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:
  • 10% Reduction of Combination of Esmeron® and Nimbex®, Group S: mean 1.21 versus 1.43 on control; difference -0.22 (95% CI -0.47 to 0.02), standardized effect d = -0.48; z-test p = 0.075.
  • 20% Reduction of Combination of Esmeron® and Nimbex®, Group L: mean 0.82 versus 1.43 on control; difference -0.61 (95% CI -0.82 to -0.40), standardized effect d = -1.55; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 10% Reduction of Combination of Esmeron® and Nimbex®, Group S and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for 20% Reduction of Combination of Esmeron® and Nimbex®, Group L than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Across the secondary outcomes, the pattern is not uniform across measures. The two reduced-dose groups had broadly similar operation-time and anesthetic-time summaries to the intubating-dose group, while the rescue-dose-per-hour outcome was lower in the reduced-dose groups, particularly in the 20% reduction group. These observations describe different aspects of the intraoperative course and should not be treated as interchangeable evidence about the primary onset-time endpoint.

The primary result concerns the time to a monitored train-of-four ratio of zero. Operation time and anesthetic time describe durations, while the rescue-dose measure describes the frequency of additional dosing relative to time. A pattern in one of these outcomes does not automatically explain or validate the pattern in another. The record does not report a joint analysis relating these secondary measures to primary onset time.

The secondary comparison results are unadjusted. In general, when several outcomes and comparisons are examined, the chance of at least one apparently notable result can increase if no multiplicity procedure is used. The registry record does not report whether adjustment was planned or applied. For that reason, secondary findings carry less weight than a prespecified primary analysis would, especially when the full testing strategy is not available. They are best understood as descriptive evidence that may help characterize the observed group patterns, not as independent confirmation of the primary comparison.

The registry record lists three secondary outcomes, but does not list inferential analyses under reported analyses. That gap limits assessment of whether the posted comparisons match the intended analysis plan or whether all planned secondary outcomes are represented. The secondary summaries add context, but they cannot establish a comprehensive account of the trial’s statistical findings.

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

• Operation Time
• Anesthetic Time
• Additional Rescue Doses Per Hour Ratio.

9. Statistical Interpretation

10. Statistical Methods Explained

Continuous outcomes are measurements that can take a range of values. Onset time, operation time and anesthetic time are reported as means with standard deviations. A mean describes the central value of the observations; the standard deviation describes how spread out individual observations are around that mean. A mean difference compares the average in one group with the average in the comparator group. Its sign depends on which group is subtracted from which, so interpretation should follow the comparison labels and the stated group order.

The primary endpoint is a time measurement, but it is analyzed in the posted results as a continuous outcome summarized by its mean and standard deviation. This approach treats the measured elapsed time as a quantitative value. The registry record does not describe a time-to-event analysis for this endpoint. Nor does it report how observations that did not reach the endpoint within the stated assessment period would have been handled.

The trial summary says that one-way ANOVA was used for statistical analysis. In general, analysis of variance compares group means by relating variation between groups to variation within groups. An overall ANOVA test addresses whether the group means show evidence of differences somewhere among the groups; by itself, it does not identify which specific pair differs. Pairwise comparisons are needed to describe particular contrasts. The registry record does not report the exact ANOVA model, follow-up comparison procedure, or whether the pairwise estimates were part of the sponsor’s analysis.

The record gives α=0.05 and β=0.2 in its methods summary. In general, alpha is the threshold used to control the chance of a false-positive finding under a specified testing procedure. Beta is the chance of failing to detect an effect of a specified size under the assumptions of a planned analysis; power is one minus beta. Those concepts depend on a defined analysis and effect assumption. The registry record does not give the original sample-size justification or the effect size used to plan enrollment, so the stated values do not establish how the original enrollment target was selected.

The posted comparison results include mean differences, confidence intervals and unadjusted p-values. A p-value, in general, describes how incompatible the data are with a specified null hypothesis under the assumptions of a statistical model. It is not the probability that the null hypothesis is true, nor does it measure the size or practical importance of an effect. Because the reported p-values are unadjusted, they do not account for the fact that several outcomes and group comparisons are considered.

A confidence interval gives a range of values compatible with the observed data under the calculation’s assumptions. In general, narrower intervals indicate greater precision, while wider intervals indicate more uncertainty. An interval that includes zero for a mean difference is consistent with no difference as well as with the other values in its range. An interval excluding zero indicates that the corresponding unadjusted comparison is inconsistent with zero under that interval procedure; it does not resolve multiplicity or other study limitations.

The variance of an outcome can differ between groups. In general, unequal variances may affect standard errors and the reliability of methods that assume equal variance. For the primary outcome, the reported standard deviations are larger in the 20% reduction group than in the other two groups. The registry record does not say whether variance assumptions were assessed or whether an alternative method was considered. This is relevant when interpreting the precision of comparisons, particularly with equal group sizes of 27.

Over-dispersion is a concern when observed variability exceeds what a statistical model assumes. In general, a model that understates variability can produce confidence intervals that are too narrow and p-values that overstate evidence. That concept is most often discussed for counts or other outcomes with a specified mean-variance relationship. The primary outcome is a continuous time measure, and the registry record does not report a model for over-dispersion. Its reported means and standard deviations still show that variability differs across the groups, so the chosen variance assumptions matter.

The record does not provide an analysis plan detailed enough to identify which population was used for each outcome, how missing observations were treated, or whether analyses followed original assignment regardless of treatment received. It also does not report interim analyses. Those details cannot be inferred from randomization or masking labels alone. The posted summary statistics support descriptive comparisons, but a fuller appraisal of the inferential analysis would require these unreported details.

11. Confidence Intervals and Precision

The primary comparison for the 10% reduction group has a 95% confidence interval from -13.82 to 48.42 seconds for the mean difference. This range includes zero and allows values on either side of no difference. The estimate is therefore not highly decisive about the direction or size of the contrast. The unadjusted p-value is 0.276, consistent with the interval’s lack of separation from zero under the reported comparison.

For the 20% reduction group, the 95% confidence interval for the mean difference runs from 126.9 to 246.1 seconds. This interval does not include zero and indicates a positive difference in mean onset time in this comparison. It nevertheless spans a range of possible magnitudes, so the point estimate should not be treated as exact. The standard deviation in that group, 147.8 seconds, is also larger than in the other groups, indicating greater observed spread in onset times.

In general, confidence intervals show both the direction and the precision of an estimate. They do not guarantee that the true effect lies in the interval, and their interpretation depends on the analysis assumptions. These are posted, unadjusted pairwise intervals; the registry record does not describe a multiplicity adjustment. Considering several comparisons can make isolated confidence intervals less conclusive than they might appear when considered alone.

The group sizes were 27 participants each. With this amount of information, estimates may remain uncertain even when a point estimate appears substantial. The intervals are useful for judging the range of differences compatible with the observed data, but they do not answer questions about generalizability, unreported analysis choices or the implications of missing observations.

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 comparisons of continuous outcomes; they are not total event counts. The accompanying planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set at the stated fraction of the observed effect. The registry record does not report the original trial’s sample-size assumptions or justification.

The 80% power column means the illustrative number of participants per arm for an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding number per arm for a 90% chance. These are planning illustrations derived from the observed effect, not observed power. They are not a retrospective measure of the trial’s success or a guarantee that a future study with that enrollment would achieve the stated power.

Rows that plan for a smaller fraction of the observed effect require more participants per arm. This is expected: smaller differences are harder to distinguish from random variation when measurement variability and other assumptions remain in place. Estimates based on the observed effect can be unstable, particularly when groups are small, so the figures should be read as conditional illustrations rather than firm recommendations. The calculations do not incorporate an adjustment for multiple comparisons, missing data, or other design features not listed among the planning assumptions.

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 = 17.300; pooled standard deviation σ = 58.345.
2. n = 2 × (1.96 + 0.842)² × 58.345² / 17.300² = 178.5, rounded up to 179 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 <- 17.3                      # observed difference in means
sigma <- 58.3453511430002                     # 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(2495038)
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 = 179 (80% power), 240 (90% power)
 75% of observed effect: n per arm = 318 (80% power), 425 (90% power)
 50% of observed effect: n per arm = 715 (80% power), 957 (90% power)
power.t.test: 179.5 
Simulated power at n = 179 per arm: 0.798 (20000 replicates)

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

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates more than one outcome, comparison or analysis. If each is assessed separately without adjustment, the overall chance of a false-positive result can be greater than the threshold used for any one test. This trial reports a primary endpoint, three secondary outcomes and comparisons of each reduced-dose group with the intubating-dose group. The comparison p-values are labeled unadjusted.

The registry record does not report a multiplicity strategy, such as a hierarchy of outcomes, a family of comparisons, or an adjustment to significance thresholds or confidence intervals. It is therefore not possible to determine whether the unadjusted comparisons were intended as confirmatory tests, exploratory analyses or descriptive summaries. The unadjusted p-values should not be interpreted as if they account for all the comparisons made.

Missing-data procedures and analysis populations are also not reported in the registry record. The record does not say whether every randomized participant contributed to every outcome, how incomplete monitoring or unavailable measurements were handled, or whether the analysis followed random assignment. These details matter because excluding participants or measurements can affect both group comparability and precision.

The record gives the trial status as completed and lists the enrolled group sizes, but that does not establish that there were no missing outcome observations. It reports no analyses under reported analyses, while the trial summary describes one-way ANOVA. The specific analysis model, assumptions, handling of missing observations, and relationship between the described method and posted comparisons are not reported in the registry record. No interim analyses are reported. These omissions limit assessment of the statistical plan and the extent to which the posted results reflect the analysis originally intended.

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 3.7% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists zero participants affected by serious adverse events in each of the three groups. It also lists zero deaths in every group. For other adverse events, the record lists zero affected participants in the intubating-dose group, zero in the 10% reduction group and three in the 20% reduction group. No serious adverse event terms are listed.

These figures describe what was entered in the registry record; they do not establish that no other events occurred or that the groups have identical safety profiles. With 27 participants in each group, the counts provide limited information about uncommon events. The record does not provide event descriptions for the three other adverse events, their severity, timing, relationship to study drugs, or how adverse events were collected. Comparisons of these counts should therefore remain descriptive and should not be treated as proof of a difference or absence of risk.

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

The results describe mean onset times and other recorded outcomes among the randomized groups in this completed trial. The primary comparison between the intubating-dose group and the 10% reduction group is uncertain: its confidence interval includes zero. The comparison with the 20% reduction group is more clearly separated from zero in the posted unadjusted estimate, with a longer mean onset time in that group. These are statements about the observed endpoint and comparisons, not broad conclusions about clinical benefit.

The study does not establish that any regimen is appropriate for an individual patient. It also does not establish equivalence between groups where a confidence interval includes zero. A failure to distinguish a difference is not proof that the groups are the same. Conversely, an unadjusted comparison with a confidence interval excluding zero does not by itself establish a clinically important effect or resolve the impact of multiple comparisons.

The outcome is a measured neuromuscular response under the monitoring and anesthesia conditions described in the registry summary. It is not a direct measure of recovery, patient-centered outcomes or overall quality of care. The registry record does not report the full analysis plan, participant characteristics, missing-data handling or longer-term outcomes, which constrains how far the results can be generalized or interpreted.

The findings are most appropriately read as an estimate of the observed differences in this small, three-group trial, with uncertainty and limitations attached. They may inform statistical understanding of how onset-time summaries differed across the tested groups, but they do not prove a mechanism, establish a causal explanation beyond the randomized comparison, or resolve questions that were not measured or reported.

17. Why This Trial Matters Statistically

This trial illustrates why a group mean alone is not enough to understand a clinical comparison. The onset-time averages differ across the groups, but the size and precision of each contrast matter. The 10% reduction comparison has an interval that includes zero, whereas the interval for the 20% reduction comparison lies above zero. Reporting estimates with intervals makes those distinctions clearer than relying on a p-value alone.

It also illustrates how outcomes can tell different parts of a story. Onset time captures a monitored response, whereas operating duration, anesthetic duration and rescue-dose use describe other aspects of the procedure. Statistical interpretation requires keeping the endpoint definitions separate rather than treating all measured outcomes as substitutes for one another.

The record also highlights the importance of a transparent analysis plan. Randomization and masking are important design features, but they do not reveal how multiple comparisons were handled, which participants were included in each analysis or what happened to missing measurements. Those details affect confidence in the interpretation and reproducibility of the findings.

Finally, planning calculations based on an observed effect are not evidence about the power of the completed trial. They can illustrate how a future design might depend on the effect size it aims to detect, while the original design assumptions remain unreported. Distinguishing planning illustrations from observed results is essential when translating a small trial’s estimates into further statistical questions.

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 record gives limited detail about the trial population beyond the listed conditions, enrollment and outcome setting. Participant characteristics, eligibility criteria, recruitment setting and reasons for exclusion are not reported in the registry record. Those omissions make it difficult to judge how representative the participants were of other populations or clinical settings.

Although the design is described as randomized and quadruple-masked, the randomization method, allocation concealment and masking procedures are not described. The record also does not explain whether all randomized participants remained in their assigned groups for analysis. These details are important for evaluating possible bias and the meaning of the group comparisons.

The posted primary outcome summaries have unequal observed standard deviations across the groups, with the largest spread in the 20% reduction group. The registry record does not state whether variance assumptions were checked or whether a method robust to unequal variance was used. The trial summary mentions one-way ANOVA, but the exact model, pairwise procedure and relationship to the posted estimates are not detailed. The record lists no reported analyses.

Multiplicity adjustment, missing-data methods, analysis populations, interim analyses and the original sample-size justification are not reported in the registry record. The limited sample size also means that estimates, particularly for less frequent safety events, may be imprecise. The safety listing does not describe the three other adverse events. These trial-specific reporting gaps limit a full assessment of precision, potential bias and the scope of conclusions.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Optimal Dose of Combination of Rocuronium and Cisatracurium — NCT02495038.
• Registry record last updated 2018-03-02; status last verified 2018-01.
• Results first posted 2017-12-20.
• 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

NCT02495038 is a completed randomized, quadruple-masked, parallel-group trial sponsored by Yonsei University. It enrolled 81 participants, with 27 in each of three groups: the combined ED95 dose, a 10% reduction of each component’s ED95 and a 20% reduction of each component’s ED95.

The primary outcome was mean time to a train-of-four ratio of zero. The mean was 212.8 seconds in the intubating-dose group, 230.1 seconds in the 10% reduction group and 399.3 seconds in the 20% reduction group. The 10% comparison interval included zero; the 20% comparison interval was above zero. Three secondary outcomes and adverse-event counts are also recorded.

The registry summary describes one-way ANOVA, but detailed analysis populations, missing-data procedures, multiplicity handling and the original sample-size justification are not reported in the registry record.