Safety and Efficacy of Oral Midazolam for Perioperative Anxiety Relief of Patients Undergoing Mohs Micrographic Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Oral Midazolam for Perioperative Anxiety Relief of Patients Undergoing Mohs Micrographic Surgery (NCT00578214), a randomized na study. The primary outcome is Patient Anxiety at Baseline.

2. Clinical Question

3. Trial Design

The registry describes a randomized, parallel-group study with quadruple masking and an enrollment of 75. It lists the study as completed. The study began in 2007-03, with primary completion in 2008-04. The registry record identifies Mayo Clinic as the sponsor and lists the phase as NA.

The study had two parts. In the randomized part, eligible patients were assigned to single-dose midazolam syrup or placebo syrup before surgery; the study summary says patients and the study team did not know the assignment. Separately, patients who were not eligible for, or declined, the randomized study could enter a prospective midazolam arm. Participants in that arm knew they were receiving midazolam, and dosing was based on weight with additional doses as needed.

This distinction matters when interpreting comparisons. Random allocation supports a fairer comparison of the randomized midazolam and placebo groups, because assignment is not chosen according to participant characteristics. The prospective group was selected through eligibility or willingness and did not have a randomized placebo comparison. Its results can describe that group, but differences from the placebo group may reflect group differences as well as treatment exposure.

The registry record does not report the original sample-size justification, detailed allocation procedures, or a statistical analysis plan. The posted analyses include calculated comparisons, but no registry-reported analyses are listed.

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

Analysis population for the primary outcome, as defined in the registry: The analysis was done on the patients who completed the assessment. One patient in the randomized midazolam arm, 2 patients in the placebo arm, and 1 patient in the prospective midazolam arm did not complete this assessment.

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 Patient Anxiety at Baseline, measured over Baseline (prior to drug administration).

The posted primary outcome is patient anxiety at baseline, before drug administration. Anxiety was assessed using a 10-point visual analog scale: 0 represents no anxiety and 10 the highest possible anxiety. Participants marked their own feeling of anxiety on the scale. The registry reports means and standard deviations for the participants who completed this assessment.

A baseline anxiety measure can describe how anxious groups were before receiving the study medication. It can also help assess whether the groups began with similar measured anxiety. It cannot, by itself, show whether anxiety changed after administration or whether a treatment caused a change. That distinction is central because the study summary describes a primary hypothesis about anxiety at 60 minutes, whereas the posted primary outcome is explicitly the pre-administration baseline measure.

Baseline values were available for 21 participants in the randomized midazolam group, 20 in the placebo group, and 30 in the prospective midazolam group. The registry notes that one randomized midazolam participant, two placebo participants, and one prospective midazolam participant did not complete the assessment. Thus the outcome summaries describe completers, rather than every person enrolled in the study.

7. Results Posted in the Registry

• Randomized Midazolam: mean 1.30 versus 1.40 on control; difference -0.10 (95% CI -1.05 to 0.85), standardized effect d = -0.06; z-test p = 0.837.
• Prospective Midazolam: mean 3.40 versus 1.40 on control; difference 2.00 (95% CI 0.81 to 3.19), standardized effect d = 0.86; 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.

Patient Alertness at Baseline

• 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:
  • Randomized Midazolam: mean 0.20 versus 0.20 on control; difference 0.00 (95% CI -0.39 to 0.39), standardized effect d = 0.00; z-test p = 1.000.
  • Prospective Midazolam: mean 0.20 versus 0.20 on control; difference 0.00 (95% CI -0.36 to 0.36), standardized effect d = 0.00; z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Randomized Midazolam 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 Prospective Midazolam and the control. The interval gives the range of effects that remain compatible with the data.

Patient Cognitive Function at 120 Minutes

• 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:
  • Randomized Midazolam: mean 26.00 versus 29.20 on control; difference -3.20 (95% CI -6.83 to 0.43), standardized effect d = -0.51; z-test p = 0.084.
  • Prospective Midazolam: mean 27.50 versus 29.20 on control; difference -1.70 (95% CI -4.22 to 0.82), standardized effect d = -0.31; z-test p = 0.186.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Randomized Midazolam 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 Prospective Midazolam and the control. The interval gives the range of effects that remain compatible with the data.

Heart Rate at 30 Minutes

• 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:
  • Randomized Midazolam: mean 61.70 versus 64.30 on control; difference -2.60 (95% CI -9.72 to 4.52), standardized effect d = -0.22; z-test p = 0.474.
  • Prospective Midazolam: mean 72.10 versus 64.30 on control; difference 7.80 (95% CI 2.14 to 13.46), standardized effect d = 0.70; z-test p = 0.007.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Randomized Midazolam 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 higher for Prospective Midazolam than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registered secondary outcomes cover alertness and cognitive function at specified assessment times, cardiovascular and respiratory measures, and pulse oximetry. The available posted summaries include baseline alertness, cognitive function at 120 minutes, and heart rate at 30 minutes. This range reflects both patient-reported or performance-related measures and physiological observations, but the secondary outcomes are not substitutes for the stated 60-minute anxiety question.

Across the available comparisons, the randomized midazolam and placebo groups have the same reported mean alertness at baseline. The randomized comparison of cognitive function at 120 minutes has an interval that includes zero. For heart rate at 30 minutes, the randomized comparison also has an interval that includes zero. The prospective group comparisons differ in some measures, but those contrasts remain nonrandomized and should not be given a causal interpretation. No overall pattern across these secondary results resolves the primary endpoint mismatch.

Secondary outcomes commonly help characterize a study beyond its main question, including possible changes in related measures and physiological observations. However, multiple outcomes and comparisons create more opportunities for apparently notable results to occur by chance. The record lists 14 outcome measures and no registry-reported analyses. Adjustment for multiplicity is not reported, so the unadjusted secondary comparisons carry less evidential weight than a clearly prespecified, appropriately analyzed primary outcome.

The secondary summaries should be read as exploratory descriptions. They may motivate questions for further evaluation, but they do not independently establish treatment benefit or safety. Their interpretation is further constrained by the small groups, incomplete outcome assessments, and the different selection process for the prospective arm.

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

• Patient Alertness at Baseline
• Patient Alertness at 60 and 120 Minutes
• Patient Cognitive Function at Baseline and 60 Minutes
• Patient Cognitive Function at 120 Minutes
• Blood Pressure at 30 Minutes
• Heart Rate at 30 Minutes
• Respiratory Rate at 30 Minutes
• Pulse Oximetry at 30 Minutes

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: anxiety is recorded on a scale and summarized with a mean and standard deviation. The mean gives the average score in a group. The standard deviation describes how dispersed individual scores are around that group average. These summaries are useful for describing the groups, but they do not by themselves show whether a difference is statistically clear or clinically important.

What does a mean difference represent?

The mean difference compares the average score in one group with the average score in the reference group. For randomized midazolam versus placebo at baseline, the recalculated mean difference is -0.1. The negative sign indicates that the randomized midazolam group's average baseline anxiety score was lower. The magnitude is small relative to the scale, but the estimate should still be interpreted with its uncertainty. The prospective comparison is also expressed as a mean difference, but its nonrandomized design limits causal interpretation.

What does the p-value tell us?

A p-value describes how compatible the observed data are with a statistical model in which the groups have no mean difference, under the assumptions of that model. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of a difference. The unadjusted p-value for the randomized baseline comparison is 0.837. The prospective comparison has an unadjusted p-value of 0.001, but that value does not resolve the selection differences between the prospective and placebo groups. A small p-value cannot turn a nonrandomized contrast into a randomized treatment estimate.

Why use a confidence interval?

A confidence interval gives a range of effect estimates compatible with the observed data and the method used to calculate it. When an interval for a mean difference includes zero, the data are compatible with no mean difference as well as with differences in either direction. When it excludes zero, that indicates a difference under the calculation's assumptions, but it does not establish causation, clinical importance, or freedom from bias. The baseline randomized interval includes zero. The prospective interval does not, but its comparison remains subject to selection bias.

What does recalculated mean?

The posted mean-difference estimates, confidence intervals, and p-values are simple unadjusted recalculations from summary statistics. They are not presented as the sponsor's own analyses. No registry-reported analyses are listed. These calculations do not account for any covariates, multiple comparisons, or analysis procedures that may have been used outside the registry record. The registry record does not report such procedures, so they should not be assumed.

Why does randomization matter?

Random assignment is intended to make treatment groups comparable, on average, apart from the assigned intervention. That supports interpreting a difference between randomized groups as an effect of assignment, subject to the analysis and missing-data assumptions. Participants in the prospective group entered by a different route and knew they were receiving midazolam. Comparing that group with placebo is therefore observational, even though both groups appear in the same record.

How should baseline be distinguished from response?

Baseline is measured before treatment. A post-treatment score measures the outcome after treatment, while a change score compares a participant's post-treatment measurement with their baseline measurement. The posted primary measure is baseline anxiety, not a post-treatment score or change. The study summary's stated hypothesis concerns anxiety at 60 minutes, so this mismatch limits how directly the posted primary result answers the stated question.

Statistical significance is not a measure of certainty that a treatment works. Interpretation depends on the endpoint, design, estimation uncertainty, missing observations, and whether analyses were planned and adjusted appropriately. Those details are incomplete in the registry record. The statistical comparisons should therefore be read as summaries of the posted data rather than as a complete account of the trial's analysis.

11. Confidence Intervals and Precision

Precision concerns how tightly the data estimate a group difference. A confidence interval that spans a broad range indicates that a range of effects remains compatible with the observed data. A narrow interval provides more precise information, although it still does not address bias or whether the outcome is the one needed to answer the clinical question.

For the randomized baseline anxiety comparison, the mean difference is -0.1 and the unadjusted p-value is 0.837. The interval crosses zero, so it includes no difference as well as possible differences in either direction. The observed means are close, but the modest number of completed assessments means the estimate should not be treated as proof that the groups were identical. Failure to distinguish a difference is not the same as demonstrating equivalence.

The prospective comparison has a larger baseline difference, but its precision does not remove the concern that its participants were selected differently. Confidence intervals describe sampling uncertainty under the calculation's assumptions; they do not correct selection bias or convert an observational contrast into a randomized one.

Most importantly, precision around a baseline comparison is not precision about a post-dose treatment effect. The primary outcome posted in the registry is measured before medication, while the study summary's hypothesis concerns anxiety at 60 minutes. The latter result is not reported in the registry record as the primary outcome. The available confidence intervals therefore cannot settle the stated treatment question.

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, not total events. The illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They are based on the observed effect, with planning scenarios for 100%, 75%, and 50% of that observed effect. The original trial's own sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the estimated participants per arm for a future study to have an 80% chance of detecting the specified effect under those assumptions. The 90% power column gives the corresponding planning target for a 90% chance. These are design calculations for hypothetical studies, not descriptions of the completed study's probability of finding a result.

Smaller effects are harder to distinguish from random variation, so the planning illustrations require more participants per arm when the assumed effect is reduced. The table includes calculations for the randomized midazolam comparison and the prospective comparison. Because the first observed baseline difference is very small, planning based on that estimate yields especially large sample-size requirements. The prospective estimate comes from a nonrandomized comparison and may not be an appropriate treatment effect for future randomized planning.

These figures are planning illustrations, not observed power. They do not establish whether the completed trial was adequately powered for its original intended endpoint, especially because the registry record does not report the trial's design assumptions and the posted primary outcome differs from the 60-minute hypothesis described in the study summary.

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 = -0.100; pooled standard deviation σ = 1.550.
2. n = 2 × (1.96 + 0.842)² × 1.550² / -0.100² = 3,769.1, rounded up to 3,770 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 <- -0.0999999999999999                      # observed difference in means
sigma <- 1.54952432734231                     # 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(578214)
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 = 3,770 (80% power), 5,046 (90% power)
 75% of observed effect: n per arm = 6,701 (80% power), 8,971 (90% power)
 50% of observed effect: n per arm = 15,077 (80% power), 20,183 (90% power)
power.t.test: 3770 
Simulated power at n = 3,770 per arm: 0.804 (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 record lists 14 outcome measures and 0 registry-reported analyses. It does not report whether the investigators prespecified a hierarchy among outcomes, adjusted for multiple testing, or used a particular approach to control the chance of false-positive findings. These details are not reported in the registry record, so no adjustment strategy should be inferred from the posted unadjusted comparisons.

Multiplicity arises when many outcomes, time points, or group comparisons are examined. Even when there is no real difference, examining many results can make at least one appear notable by chance. This is why an unadjusted p-value for a secondary result should not be interpreted as though it were the only planned test. The concern applies particularly to the multiple secondary measures and time points listed in the record.

Missing outcome data also affect interpretation. For baseline anxiety, the registry says the analysis included participants who completed the assessment and identifies one missing assessment in randomized midazolam, two in placebo, and one in prospective midazolam. It does not report the reasons for these missing measurements or whether participants with and without assessments differed. The posted baseline comparison is therefore a completer analysis, and the possible effect of missingness cannot be assessed from the registry record.

The primary anxiety result is reported at baseline, while the study summary describes a 60-minute primary hypothesis. The record does not explain this discrepancy or report a post-dose anxiety result as the primary outcome. The original statistical analysis plan, handling of missing data, covariate adjustment, and any interim analyses are not reported in the registry record. Without those details, the posted summaries should not be treated as a complete account of the planned analysis.

The randomized and prospective populations also require separate interpretation. The former supports a randomized treatment comparison; the latter reflects eligibility or willingness to participate in the randomized part. Combining their results or treating their comparisons as interchangeable would obscure these design differences.

15. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events in 22 participants at risk in the randomized midazolam group and 22 at risk in the placebo group; no serious adverse events are listed for either group. In the prospective midazolam group, 31 participants were at risk and no serious adverse events are listed. These figures describe the posted serious-event counts during the registry's safety reporting period, which is not further characterized in the record.

For other adverse events, the registry lists none among the 22 participants at risk in randomized midazolam or among the 22 at risk in placebo. In the prospective midazolam group, one other adverse event is listed among 31 participants at risk. Serious adverse event counts and other adverse event counts are separate categories; the single other event is not listed as serious.

Zero recorded serious events in these groups does not establish that serious events cannot occur. The groups are limited in size, and the registry record does not provide event descriptions for the listed other event, detailed ascertainment procedures, or a comparison adjusted for the prospective group's nonrandomized design. The safety counts should be read as registry reports, not as proof of safety or as a basis for medical advice.

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

The record documents a study of oral midazolam in the setting of Mohs micrographic surgery, using a randomized midazolam-versus-placebo component and a separate prospective midazolam component. It posts baseline anxiety summaries and selected secondary outcome summaries, as well as adverse event counts. The randomized baseline anxiety means were similar in the posted summaries; the prospective group began with a higher mean.

These observations do not answer whether midazolam reduced anxiety at 60 minutes. Baseline measurement occurs before the intervention, and the posted primary outcome does not report the post-dose endpoint described in the study summary. The baseline difference in the prospective arm is also not an estimate of a drug effect because that arm was not randomized against placebo.

The record does not establish that the groups were equivalent, nor does it establish that any observed difference is clinically important. A p-value does not measure clinical importance, and a confidence interval does not eliminate design bias. The modest assessment counts, missing baseline assessments, multiple outcomes, and absence of registry-reported analysis details all affect how confidently the summaries can be interpreted.

Similarly, the adverse-event counts show what was recorded for the groups in the registry; they do not prove that no risk exists. The absence of reported serious events in these groups should be understood in the context of the group sizes and incomplete safety detail.

The most defensible reading is descriptive: the posted baseline anxiety summaries show a small randomized-group difference and a larger nonrandomized difference, while the intended post-dose primary question is not answered by the posted primary measure. Nothing in these results alone warrants a conclusion that treatment works or does not work.

17. Why This Trial Matters Statistically

This trial is statistically instructive because the stated clinical hypothesis and the posted primary outcome are not aligned. The study summary describes anxiety at 60 minutes as the principal question, but the primary outcome result is anxiety before drug administration. That distinction demonstrates why endpoint timing is as important as endpoint name: a measure collected before treatment cannot estimate a post-treatment response.

The record also places a randomized study beside a prospective arm. Both contain midazolam recipients, but the groups were assembled differently. Randomization supports causal interpretation of the randomized comparison, subject to the outcome and analysis; a prospectively observed group selected by eligibility or willingness does not have the same protection against confounding. The higher baseline anxiety in that group illustrates why group formation matters when interpreting differences.

The record further shows how uncertainty, missing measurements, multiple outcomes, and limited analysis reporting shape conclusions. The randomized baseline comparison does not demonstrate a meaningful difference, but neither does it establish equivalence. Secondary comparisons may be informative descriptively, yet their unadjusted nature and multiplicity lower the strength of isolated findings. The posted safety counts likewise provide observed event information, not definitive evidence that risks are absent.

For clinical researchers, the central lesson is to align the estimand, outcome timing, and analysis with the question being asked. Statistical summaries are only as relevant as the endpoint they estimate and the design supporting the comparison.

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.

A key limitation is that the posted primary measure is baseline anxiety, while the study summary states a hypothesis about anxiety at 60 minutes. The registry record does not report the 60-minute anxiety result as the primary outcome or explain the difference. This prevents the posted primary comparison from answering the central treatment question as described.

The prospective arm is not randomized and includes patients who were ineligible for or declined the randomized study. Its baseline and secondary comparisons with placebo may be affected by selection and other group differences. Participants in that arm knew they were receiving midazolam, unlike the masked randomized comparison described in the study summary.

The baseline anxiety analysis includes completers, with missing assessments noted in each group. Reasons for missingness and methods for handling missing data are not reported. The registry record also does not report the original sample-size justification, detailed analysis plan, multiplicity strategy, interim analyses, or covariate adjustments.

There are numerous listed outcomes and time points, while registry-reported analyses are absent. The unadjusted recalculations are therefore limited summaries and should not be assumed to reproduce the investigators' complete analysis. Safety information is also sparse: the record gives event counts but limited detail about event descriptions and ascertainment. These limitations constrain both causal and safety interpretations.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety and Efficacy of Oral Midazolam for Perioperative Anxiety Relief of Patients Undergoing Mohs Micrographic Surgery — NCT00578214.
• Registry record last updated 2012-02-09; status last verified 2012-02.
• Results first posted 2012-02-09.
• 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

NCT00578214 is a completed Mayo Clinic study of oral midazolam around Mohs micrographic surgery for skin cancer. The registry describes a randomized, quadruple-masked, parallel-group component and a separate prospective midazolam arm, with enrollment of 75.

The posted primary outcome is baseline anxiety on a 10-point visual analog scale, measured before drug administration. The randomized midazolam and placebo groups had similar baseline means; the prospective group had a higher mean, but it was not randomized against placebo. The study summary's stated 60-minute anxiety hypothesis is not answered by this baseline outcome.

The record lists secondary outcomes and adverse-event counts, but no registry-reported analyses. The posted summaries are best treated as descriptive, with interpretation limited by the endpoint mismatch, the nonrandomized prospective arm, missing assessments, multiple outcomes, and unreported analysis details.