Safety of Sugammadex for the Reversal of Neuromuscular Blockade in American Society of Anesthesiologists (ASA) Class 3 or 4 Participants (MK-8616-145): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of Sugammadex for the Reversal of Neuromuscular Blockade in American Society of Anesthesiologists (ASA) Class 3 or 4 Participants (MK-8616-145) (NCT03346057), a randomized phase 4 study. The primary outcome is Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events.

2. Clinical Question

3. Trial Design

This was a Phase 4, randomized, triple-masked, parallel-group, active-comparator controlled clinical trial. Its stated purpose was to evaluate sugammadex safety for reversal of neuromuscular blockade induced by rocuronium or vecuronium in adults with ASA Physical Status Class 3 or 4 in a surgical setting. The registry lists enrollment of 344, a start date of 2017-12-20, primary completion on 2019-09-04, and status as completed.

The listed study interventions were sugammadex 2 mg/kg, 4 mg/kg, and 16 mg/kg, and neostigmine plus glycopyrrolate. The three sugammadex regimens were described as single intravenous doses. The active comparator was a single intravenous dose of neostigmine 50 μg/kg, up to 5 mg maximum, plus glycopyrrolate 10 μg/kg, up to 1 mg maximum. Rocuronium and vecuronium were also listed as interventions; the trial description identifies them as the neuromuscular blockade agents whose effects were being reversed.

For the primary endpoint, the posted group results include 105 participants in the sugammadex 2 mg/kg group, 107 in the 4 mg/kg group, 68 in the 16 mg/kg group, and 51 in the neostigmine plus glycopyrrolate group. These are the group sizes reported with that outcome, not a reconstruction of the overall enrollment. The primary population is defined as all randomized participants who received at least one dose of study intervention. Details about how randomization was generated, how masking was implemented, allocation ratios, or any stratification factors 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.

Before assignment: Of 344 participants randomized to the study, 331 received at least one dose of study treatment (All Treated Population) and were evaluable for all safety analysis.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All randomized participants who received at least one dose of study intervention

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 participants

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Treatment-Emergent Sinus Bradycardia Events, measured over Up to approximately 35 minutes post-administration.

The primary endpoint was the percentage of participants with treatment-emergent sinus bradycardia events. Continuous electrocardiogram (ECG) monitoring was used to identify events up to approximately 35 minutes post-administration. An event was defined as a heart rate <60 bpm that had also decreased more than 20% compared with the participant’s baseline heart rate, sustained for at least 1 minute after administration of study intervention. The event did not necessarily have to be classified as an adverse event; that determination was left to investigator judgment.

This endpoint focuses on an objectively monitored rhythm change during a specified period after reversal treatment. As a general statistical point, a prespecified operational definition helps make an event count reproducible: it clarifies the threshold, the required duration, and the time window in which events qualify. The percentage expresses the observed frequency relative to the participants included in each group’s analysis.

The endpoint addresses a particular acute cardiac safety signal, not every possible cardiac event or all aspects of general safety. It also does not by itself establish whether an event was caused by the study intervention. Attribution, clinical significance, and the broader safety profile require information beyond this event percentage.

7. Results Posted in the Registry

• Sugammadex 4 mg/kg: 1.9% (2/107) versus 1.0% (1/105) on control; risk difference 0.9 percentage points (95% CI -2.3 to 4.1), risk ratio 1.96 (0.18–21.32); unadjusted two-proportion z-test p = 0.572.
• Sugammadex 16 mg/kg: 7.4% (5/68) versus 1.0% (1/105) on control; risk difference 6.4 percentage points (95% CI -0.1 to 12.9), risk ratio 7.72 (0.92–64.66); unadjusted two-proportion z-test p = 0.025.
• Neostigmine + Glycopyrrolate: 7.8% (4/51) versus 1.0% (1/105) on control; risk difference 6.9 percentage points (95% CI -0.7 to 14.5), risk ratio 8.24 (0.94–71.81); unadjusted two-proportion z-test p = 0.022.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports the primary outcome as a percentage of participants with an event, with the endpoint defined by ECG monitoring and a specific heart-rate threshold, change from baseline, and duration. The reported percentages describe the observed proportion in each study group. In general, a proportion is a natural summary when the outcome is whether each participant experienced a defined event during a stated observation period.

What does a risk difference describe?

A risk difference compares the event proportions in two groups by subtracting one proportion from the other. It is expressed on the absolute probability scale. A positive or negative value depends on the order of the groups in the comparison, so the group order must be read alongside the estimate. The recalculated contrasts in the posted results are unadjusted: they are direct comparisons based on the group-level event counts and denominators, without the sponsor’s stratified analysis method.

For sugammadex 4 mg/kg versus sugammadex 2 mg/kg, the recalculated risk difference is 0.009, with a 95% confidence interval from -0.022 to 0.041. For sugammadex 16 mg/kg versus sugammadex 2 mg/kg, the recalculated estimate is 0.064, with an interval from -0.001 to 0.129. For neostigmine plus glycopyrrolate versus sugammadex 2 mg/kg, it is 0.069, with an interval from -0.007 to 0.145. The uncertainty intervals are wide in relation to the point estimates, and each includes values on both sides of zero. The unadjusted p-values are 0.572, 0.025, and 0.022 in the same comparison order.

How should the relative measures be understood?

The recalculated results also include risk ratios and odds ratios. A risk ratio compares the event probabilities as a ratio; an odds ratio compares the odds of an event. These are relative measures, unlike the absolute risk difference. The ratios can appear large when one group has few events, and their confidence intervals are especially broad in these comparisons. For example, the reported recalculated risk ratio for sugammadex 16 mg/kg versus sugammadex 2 mg/kg is 7.721, with a confidence interval from 0.922 to 64.66; the corresponding odds ratio is 8.254, with a confidence interval from 0.943 to 72.27. Such imprecision means that the point estimate alone is not a stable account of the possible relative association.

For rare or infrequent outcomes, small changes in event counts can materially affect both absolute and relative estimates. General statistical reasoning therefore favors examining the observed event numbers, group denominators, effect estimates, confidence intervals, and analysis method together rather than interpreting a p-value in isolation.

What does the sponsor’s method add?

The sponsor reports estimated differences in percentage using the stratified Miettinen & Nurminen method. This is a method for comparing proportions while accounting for stratification. The registry record does not identify the strata or give enough detail to reconstruct the sponsor’s analysis. Its reported contrasts are -6.7, -6.2, and -2.0 percentage points for sugammadex 2 mg/kg, 4 mg/kg, and 16 mg/kg, respectively, each compared with neostigmine plus glycopyrrolate. Their confidence intervals and p-values are reported with those estimates.

The sponsor’s analysis is not interchangeable with the simple unadjusted recalculations. A difference in method, comparison ordering, or analysis details can lead to different estimates and inference. The record explicitly flags a discrepancy; accordingly, the sponsor’s own analysis takes precedence. The recalculations remain useful as a transparent unadjusted check, but they should not replace the sponsor-reported results.

What does a confidence interval communicate?

In general, a confidence interval describes the range of estimates reasonably compatible with the observed data under the method’s assumptions. It conveys uncertainty about the magnitude and direction of an effect. An interval that includes zero for a difference does not establish that the groups are equivalent; it means the data and method do not rule out zero difference at the stated confidence level. An interval that excludes zero is not, by itself, evidence of clinical importance or causation.

The primary outcome has limited event counts: the recalculated comparisons use one event in the sugammadex 2 mg/kg group, two in the 4 mg/kg group, five in the 16 mg/kg group, and four in the neostigmine plus glycopyrrolate group. With event counts of this size, estimates can be sensitive to individual outcomes. The posted confidence intervals, especially the broad intervals for relative measures, make that uncertainty visible.

10. Confidence Intervals and Precision

The precision of an estimate depends on how much information the data contain. For a binary event, the number of observed events and the group denominators both matter. The primary event counts used in the recalculated comparisons were one for sugammadex 2 mg/kg, two for sugammadex 4 mg/kg, five for sugammadex 16 mg/kg, and four for neostigmine plus glycopyrrolate. These counts are small, so the estimated differences and ratios have considerable uncertainty.

The sponsor’s 95% confidence interval for sugammadex 2 mg/kg versus neostigmine plus glycopyrrolate is -17.5 to -0.8 for the estimated difference in percentage. For sugammadex 4 mg/kg versus neostigmine plus glycopyrrolate, the interval is -17.3 to 0.2; for sugammadex 16 mg/kg versus neostigmine plus glycopyrrolate, it is -17.8 to 8.6. The latter two intervals include zero. The unadjusted recalculated difference intervals also span zero for each comparison against sugammadex 2 mg/kg, including an upper or lower endpoint very near zero in some cases.

In general, a confidence interval is more informative than a point estimate alone because it shows the range of effect sizes compatible with the data under the analysis method. Wide intervals indicate that the data do not pin down the effect precisely. A result near zero does not mean the true difference must be zero, and an interval that includes zero does not demonstrate equality. Conversely, a statistically distinguishable estimate does not automatically establish that the difference is important in clinical practice.

The relative-effect intervals are particularly broad: the recalculated risk ratios and odds ratios for comparisons with sugammadex 2 mg/kg extend from values near or below no relative difference to much larger values. This reflects the limited event information and makes strong conclusions about relative differences inappropriate. The precision is also limited to the endpoint and observation window defined in the registry; it does not quantify other safety outcomes or events outside that period.

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 sample-size planning figures are participants per arm, not total events. They are illustrations based on the observed effect, not the trial’s original design calculations. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The trial’s own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the planned participants per arm for a hypothetical study to have an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding number for a 90% chance. These are planning quantities: they do not describe the probability that the completed trial detected an effect, and they are not observed power.

The rows describe planning for 100%, 75%, and 50% of the observed effect. For the sugammadex 4 mg/kg comparison with sugammadex 2 mg/kg, the figures range from 2,597 participants per arm for 80% power and 3,476 for 90% power at 100% of the observed effect, to 8,722 and 11,676 when planning for 50% of the observed effect. For sugammadex 16 mg/kg versus sugammadex 2 mg/kg, the corresponding figures are 152 and 203 at 100%, and 381 and 509 at 50%. For neostigmine plus glycopyrrolate versus sugammadex 2 mg/kg, they are 138 and 184 at 100%, and 344 and 459 at 50%.

These calculations are sensitive to the observed effect used as their starting point. Smaller effects require more participants to detect under the same assumptions. Since the starting estimates come from sparse event counts and are imprecise, the planning figures should be treated as illustrations of how assumptions affect sample size, not as firm recommendations or a reconstruction of the trial’s design.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.010; treatment proportion p₁ = 0.019; average p̄ = 0.014.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.1668 = 0.3269.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.1667 = 0.1403.
4. n = (0.3269 + 0.1403)² / (0.0092)² = 2,596.6, rounded up to 2,597 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
p0 <- 0.00952380952380952                          # control proportion
p1 <- 0.0186915887850467                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(3346057)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 2,597 (80% power), 3,476 (90% power)
 75% of observed effect: n per arm = 4,247 (80% power), 5,685 (90% power)
 50% of observed effect: n per arm = 8,722 (80% power), 11,676 (90% power)
power.prop.test: 2596.6 
Simulated power at n = 2,597 per arm: 0.807 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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. Analyses Reported by the Sponsor

The sponsor’s posted comparisons use the stratified Miettinen & Nurminen method and report estimated differences in percentage for each sugammadex dose versus neostigmine plus glycopyrrolate. The results are -6.7, with a 95% confidence interval from -17.5 to -0.8 and p = 0.026 for sugammadex 2 mg/kg; -6.2, with an interval from -17.3 to 0.2 and p = 0.058 for sugammadex 4 mg/kg; and -2.0, with an interval from -17.8 to 8.6 and p = 0.730 for sugammadex 16 mg/kg.

The recalculated results use unadjusted comparisons and do not fully match the sponsor’s reported analyses. The recalculated comparisons use sugammadex 2 mg/kg as the reference for the other groups, whereas the sponsor reports each sugammadex group compared with neostigmine plus glycopyrrolate. The record flags a discrepancy, so the sponsor’s own analysis takes precedence. The unadjusted recalculations can be read as supplementary checks, not as substitutes for the reported sponsor analysis.

Neither analysis alone establishes causation or clinical importance. The sponsor’s intervals and p-values should be interpreted alongside the endpoint definition, sparse event counts, and uncertainty in the estimated differences.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists 6 outcome measures and 18 analyses, but reports no secondary outcomes. The multiplicity procedure, if any, is not reported in the registry record. It is therefore unclear whether the reported p-values were adjusted for testing multiple outcomes or comparisons, or whether a testing hierarchy was specified. When multiple comparisons are examined, the chance of at least one apparently unusual result can increase; as a general statistical point, the interpretation of isolated p-values depends partly on how many analyses were planned and how they were handled.

The record identifies the primary analysis population as all randomized participants who received at least one dose of study intervention. The primary outcome’s group sizes are reported for that population. The handling of missing ECG measurements, incomplete monitoring, withdrawals, or other missing endpoint data is not reported in the registry record. Details about exclusions after randomization, adherence to assigned intervention, and any sensitivity analyses for missing data are also not reported.

The sponsor’s analysis is described as stratified, but the stratification variables are not reported in the registry record. The method used for the unadjusted recalculations is not the same as the sponsor’s stratified method, and the reported results differ. The record flags this discrepancy, so the sponsor analysis takes precedence for interpretation of the trial’s own reported comparisons.

Interim analyses, stopping rules, prespecified subgroup analyses, and the statistical plan for multiplicity are not reported in the registry record. Their absence from the posted record should not be taken to mean that such procedures were or were not used. The available information supports interpretation of the specified primary outcome and posted analyses, but does not establish how all planned statistical decisions were made.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: small intestinal obstruction (2.0%), catheter site haemorrhage (2.0%), abdominal wound dehiscence (2.0%), postoperative ileus (2.0%), impaired healing (1.9%).

The registry lists serious adverse event figures by group. For sugammadex 2 mg/kg, 16 participants are recorded with serious adverse events among 105 at risk; for sugammadex 4 mg/kg, 12 among 107; for sugammadex 16 mg/kg, 9 among 68; and for neostigmine plus glycopyrrolate, 4 among 51. The record also lists deaths as 1, 2, 0, and 0 in those groups, respectively. These figures are descriptive counts and do not establish that an event was caused by the intervention.

Other adverse event counts are also posted: 89 among 105 for sugammadex 2 mg/kg, 89 among 107 for sugammadex 4 mg/kg, 60 among 68 for sugammadex 16 mg/kg, and 41 among 51 for neostigmine plus glycopyrrolate. Serious adverse events and other adverse events are separate registry categories; the posted counts should not be combined.

The listed serious-event terms include small intestinal obstruction, catheter site haemorrhage, abdominal wound dehiscence, and postoperative ileus, each at 2.0%, and impaired healing and pneumonia aspiration, each at 1.9%. The registry record does not provide attribution details in these summary figures. Counts and listed terms are useful for describing what was recorded, but do not on their own permit a causal comparison or a complete assessment of safety.

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

The results describe the frequency of a narrowly defined, treatment-emergent sinus bradycardia event during continuous ECG monitoring up to approximately 35 minutes after intervention among participants with ASA Class 3 or 4. The observed percentages were 1.0% with sugammadex 2 mg/kg, 1.9% with sugammadex 4 mg/kg, 7.4% with sugammadex 16 mg/kg, and 7.8% with neostigmine plus glycopyrrolate. These are descriptive findings for the posted endpoint and study groups.

The sponsor-reported comparison of sugammadex 2 mg/kg with neostigmine plus glycopyrrolate has a confidence interval excluding zero and p = 0.026. The sponsor’s other comparisons have confidence intervals that include zero, with p = 0.058 and p = 0.730. These inferential results should be interpreted in light of the small event counts and the uncertainty in the estimates. The registry record flags a discrepancy between sponsor-reported analyses and unadjusted recalculations; the sponsor’s own analysis takes precedence.

The results do not establish that a treatment caused or prevented an event. Nor do they show that the groups are equivalent when a confidence interval includes zero. The trial’s primary endpoint is not a complete measure of cardiac safety, general safety, or longer-term outcomes. It also does not answer questions about events outside the monitoring period or about populations other than the described ASA Class 3 or 4 surgical participants.

General statistical interpretation requires distinguishing evidence about a particular measured outcome from broader claims. A point estimate is the observed contrast under a specified method; its confidence interval expresses uncertainty around that contrast. Neither a nominal p-value nor a single endpoint substitutes for evaluation of the full design, analysis plan, adverse-event profile, and clinical context.

17. Why This Trial Matters Statistically

This trial illustrates several important statistical issues in safety research. The primary outcome is a binary event with relatively few observed cases. In that setting, group percentages can differ noticeably even when the underlying event rates remain uncertain, and relative estimates can be especially unstable. Considering event counts, denominators, effect estimates, and confidence intervals together gives a more complete account than focusing on percentages or p-values alone.

The record also demonstrates why the analysis method and comparison direction matter. The sponsor reports stratified differences with neostigmine plus glycopyrrolate as the comparator, while the recalculated results are unadjusted contrasts using sugammadex 2 mg/kg as the reference for the other groups. Those approaches answer related but not identical statistical questions. Because a discrepancy is flagged, the sponsor’s reported analysis takes precedence.

Finally, the sample-size illustrations show how planning depends on the effect size a future study is intended to detect. Smaller effects require more participants under the stated assumptions. When the observed effect is based on sparse events and has wide uncertainty, planning directly from that estimate is only illustrative. The trial is therefore a useful example of the limits of interpreting rare safety outcomes from a single study, especially when missing-data and multiplicity procedures are not described in the registry record.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary endpoint captures a specific rhythm event under a defined threshold and monitoring period. It does not represent all cardiac events, all adverse events, or longer-term safety. The endpoint may or may not have been considered an adverse event, according to investigator judgment, so the event measure and adverse-event classification are not necessarily identical.

Observed event counts for the primary comparisons were one, two, five, and four across the sugammadex 2 mg/kg, 4 mg/kg, and 16 mg/kg groups and the neostigmine plus glycopyrrolate group, respectively. Estimates based on few events have limited precision; the wide intervals, particularly for relative measures, reflect that uncertainty. The group denominators also differ across the reported comparisons, and the registry does not explain the reasons for those differences.

The record flags a discrepancy between the sponsor’s stratified analysis and unadjusted recalculations. The sponsor’s analysis takes precedence, but the registry record does not identify the stratification variables or give enough detail to independently reproduce that method. Multiplicity handling, missing-data procedures, interim analyses, and the original sample-size assumptions are not reported in the registry record.

The registry identifies the target population as adults with ASA Class 3 or 4 in a surgical setting. Findings should not automatically be generalized beyond that population, intervention setting, endpoint definition, or observation window. The posted summary also does not provide enough information to assess event attribution or all clinical circumstances surrounding the serious adverse events.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety of Sugammadex for the Reversal of Neuromuscular Blockade in American Society of Anesthesiologists (ASA) Class 3 or 4 Participants (MK-8616-145) — NCT03346057.
• Registry record last updated 2020-10-08; status last verified 2020-10.
• Results first posted 2020-10-08.
• 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

NCT03346057 is a completed Phase 4 randomized, triple-masked, parallel-group, active-comparator controlled trial of sugammadex for reversal of neuromuscular blockade in adults with ASA Class 3 or 4. The registry lists enrollment of 344, a start date of 2017-12-20, and primary completion on 2019-09-04.

The primary endpoint was the percentage of participants with treatment-emergent sinus bradycardia up to approximately 35 minutes after intervention. Posted rates ranged from 1.0% for sugammadex 2 mg/kg to 7.8% for neostigmine plus glycopyrrolate. The sponsor reports stratified comparisons; because the record flags a discrepancy with unadjusted recalculations, the sponsor’s own analysis takes precedence. Event counts are limited, and the reported estimates have meaningful uncertainty.