Pilot Study: Preoperative Nicotine Lozenges: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pilot Study: Preoperative Nicotine Lozenges (NCT00586482), a randomized phase 4 study. The primary outcome is Exhaled Carbon Monoxide Concentration.

2. Clinical Question

The clinical question is about a short preoperative period, not long-term smoking behavior. Exhaled carbon monoxide was the primary outcome, measured in parts per million. Self-reported abstinence on the morning of surgery was posted as a secondary outcome.

The study compared nicotine lozenges with placebo in a randomized, parallel-group design. Its pilot designation and stated purpose matter when interpreting the findings: the registry describes feasibility and potential effect size as goals, rather than establishing a definitive estimate for a larger population. The registry record does not report further details of the eligible population, such as age criteria or the types of surgery included.

3. Trial Design

This was a Phase 4 randomized, quadruple-masked, parallel-group pilot study sponsored by Mayo Clinic. The registry lists 46 participants enrolled and the trial status as completed. The recorded start was 2006-08 and primary completion was 2013-01. The registry record does not specify which groups of people were masked.

Participants were assigned to nicotine lozenges or placebo lozenges. The active lozenges were listed as 2 or 4 mg and were taken without restriction by mouth from 7 pm the evening before surgery until surgical admission the next day. The placebo lozenges matched the active lozenges in appearance. Abstinence advisement was also listed as a behavioral intervention. The registry describes the study goal as assessing feasibility and potential effect size for lozenges as an adjunct to maintaining brief preoperative abstinence, defined as not smoking on the day of surgery.

The primary outcome was mean exhaled carbon monoxide concentration on the morning of surgery, pre-operatively. The secondary outcome posted in the registry was self-reported abstinence at that same time. The primary result includes 22 participants in the nicotine-lozenge arm and 24 in the placebo arm. The registry record does not report the reasons for the difference between the enrollment total and the numbers contributing to the posted outcome, nor does it provide a participant flow account.

The registry record does not report the original sample-size justification, the planned statistical analysis details beyond the sponsor’s posted tests, or whether interim analyses were conducted. Those omissions limit conclusions about how the trial was originally planned and how the posted analyses relate to any prespecified plan.

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 Exhaled Carbon Monoxide Concentration, measured over Morning of surgery, pre-operatively.

The primary endpoint was mean exhaled carbon monoxide concentration, measured in parts per million on the morning of surgery before the operation. Exhaled carbon monoxide is an objective measure used to assess recent exposure to cigarette smoke. In a study focused on abstaining from smoking on the day of surgery, it offers a measurement related to recent smoking that does not rely solely on participants’ reports.

The registry reports a mean and standard deviation for each arm. The nicotine-lozenge arm had a mean of 8.3 parts per million (standard deviation 7.5), based on 22 participants. The placebo arm had a mean of 12.7 parts per million (standard deviation 10.9), based on 24 participants. The unadjusted mean difference, expressed as nicotine lozenges minus placebo, was -4.4 parts per million.

This endpoint is not identical to the secondary measure of self-reported abstinence. Carbon monoxide concentration is a continuous measurement, while abstinence is recorded as a yes-or-no outcome. Neither measure alone describes longer-term smoking behavior. The registry record does not report a threshold for classifying a carbon monoxide value as abstinent, so the continuous endpoint should be interpreted as the reported concentration rather than as a count of participants who met a cutoff.

7. Results Posted in the Registry

• Nicotine Lozenges: mean 8.30 versus 12.70 on control; difference -4.40 (95% CI -9.77 to 0.97), standardized effect d = -0.47; z-test p = 0.108.

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.

Self-reported Abstinence

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Nicotine Lozenges: 72.7% (16/22) versus 54.2% (13/24) on control; risk difference 18.6 percentage points (95% CI -8.7 to 45.8), risk ratio 1.34 (0.86–2.10); unadjusted two-proportion z-test p = 0.193.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Nicotine Lozenges and the control. The interval gives the range of effects that remain compatible with the data.

The registry posts one secondary outcome: self-reported abstinence on the morning of surgery, before the operation. Descriptively, the nicotine-lozenge group had more participants reporting abstinence than the placebo group. The recalculated risk-difference interval includes zero, and the sponsor’s Fisher Exact test and the recalculated test do not provide strong evidence of a clear group separation.

The secondary outcome is related to the primary endpoint because both address smoking or abstinence in the preoperative period. They are not interchangeable: one is self-reported abstinence, while the primary endpoint is a measured carbon monoxide concentration. The results point in the same descriptive direction, but the relationship between them does not establish that one measure confirms the other. Their uncertainty and the small enrollment remain central to interpretation.

Unadjusted secondary results generally carry less weight than a designated primary outcome because examining multiple outcomes can increase the chance of finding an apparently notable result by chance. In general, multiplicity procedures can account for the number of comparisons, but the registry record does not report whether any such procedure was planned or used. The secondary finding should therefore be considered exploratory rather than as independent confirmation of the primary comparison.

The registry record lists five outcome measures and five analyses overall, but only one secondary outcome is posted in the secondary results. It does not report the status or findings of the other outcome measures in a way that supports further interpretation. No additional secondary endpoint pattern should be inferred from the count of measures alone.

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

• Self-reported Abstinence

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: each participant has a measured exhaled carbon monoxide concentration, and the registry reports the group mean and standard deviation. A mean describes the central value of a group, while a standard deviation describes how dispersed individual measurements are around that mean. The reported spread is substantial in both arms, particularly in relation to the observed difference between their means, so individual measurements vary considerably within each group.

What does the mean difference represent?

The mean difference compares the nicotine-lozenge mean with the placebo mean, using nicotine lozenges minus placebo. The estimate of -4.4 parts per million therefore indicates that the observed mean was lower in the nicotine-lozenge arm. A difference is an estimate from these participants; it is not a guarantee that the same difference would appear in another sample. The confidence interval communicates how uncertain that estimate is under the calculation’s assumptions.

Why use a t-test?

The sponsor reported a two-sided t-test for the primary comparison. In general, a two-sample t-test evaluates whether the group means are compatible with a null model of no difference, while accounting for variability and sample size. A two-sided test considers differences in either direction rather than testing only whether one group’s mean is lower. The registry record does not report further details about the specific t-test implementation or any adjustment for other factors.

The recalculated comparison is an unadjusted calculation from the posted summary statistics. It does not control for participant characteristics or other covariates. The recalculated p-value was 0.108, while the sponsor reported 0.12. These are close but not identical values. The registry record does not report the reason for the difference, and the sponsor’s reported test remains the trial’s own analysis.

How should the p-value be read?

In general, a p-value describes the compatibility of the observed data, or more extreme data, with a null model and the assumptions used for the test. A value above a chosen threshold is not proof that there is no difference. Nor does a value below a threshold quantify the size, practical importance, or probability of a treatment effect. The p-values should therefore be read alongside the estimated difference and its confidence interval, rather than in isolation.

What does the standardized effect describe?

The recalculation reports a standardized mean difference of -0.467. In general, standardizing a mean difference expresses it relative to a measure of variability, making the estimate less dependent on the original measurement units. The sign reflects the same direction as the unstandardized estimate, with lower values in the nicotine-lozenge arm. A standardized effect is still an estimate from this small sample and does not remove uncertainty or establish a clinical interpretation.

How is the secondary outcome analyzed?

Self-reported abstinence is binary: a participant is recorded as abstinent or not abstinent. The posted counts were 16 participants in the nicotine-lozenge arm and 13 in the placebo arm. The recalculated risk difference was 0.186, defined as the abstinence proportion in the nicotine-lozenge arm minus that in the placebo arm. Its confidence interval was -0.087 to 0.458. The recalculated unadjusted p-value was 0.193, while the sponsor reported a Fisher Exact p-value of 0.23.

Fisher’s exact test is a method for comparing categorical outcomes between groups. In general, it calculates a test result using the observed counts and is often used when counts are limited. A risk difference gives an absolute comparison between group proportions; the reported interval shows the uncertainty around that comparison. The registry also posts relative measures, but any ratio estimate can be unstable when based on small group counts. No adjusted secondary analysis is reported.

Why does over-dispersion matter?

In general, over-dispersion means that observed variability exceeds what a statistical model assumes. When a model understates variability, its uncertainty estimates can be too narrow and its test results too optimistic. The primary endpoint is analyzed as a continuous outcome with group means and standard deviations, and the registry does not report a separate over-dispersion assessment. The broad spread in the posted values reinforces the need to attend to uncertainty, but does not by itself establish a particular model problem.

What is not documented?

The registry record does not report the original sample-size justification, interim analyses, a full statistical analysis plan, adjustment for multiple outcomes, missing-data procedures, or a detailed analysis-population definition. Those details should not be inferred from the tests or calculations posted. The planning illustrations are based on the observed effect and stated planning assumptions; they are not evidence that the original trial was designed around those assumptions.

11. Confidence Intervals and Precision

The primary mean-difference estimate is -4.4 parts per million, with a confidence interval from -9.77 to 0.970. A confidence interval is a range of values compatible with the data and the method used to calculate it. In general, it reflects sampling uncertainty; it does not mean that each value in the interval is equally likely, nor does it include every possible source of uncertainty, such as problems with measurement or missing data.

Because the primary interval crosses zero, the posted result is compatible with no difference as well as with differences in either direction. The interval reaches from a sizable lower mean in the nicotine-lozenge arm to a small higher mean. That breadth means the study does not estimate the between-group difference precisely. The group standard deviations, 7.5 and 10.9, also describe considerable variation among participants’ measurements.

For self-reported abstinence, the risk-difference interval runs from -0.087 to 0.458. It too includes zero and covers a broad range of possible between-group differences. This indicates that the secondary estimate is imprecise. The number of participants contributing to the outcome was 22 in the nicotine-lozenge arm and 24 in the placebo arm, so the estimates are based on a small study population.

Confidence intervals do not resolve questions about how representative the participants were, whether data were missing, or whether the reported analyses were prespecified. The registry record does not report those details. The intervals should be read as uncertainty around the posted comparisons under their calculation methods, not as a complete account of uncertainty about the study.

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 describe participants per arm, not total events. They are illustrations based on the observed primary effect and the stated planning assumptions: a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect equal to a stated fraction of the observed effect. The registry record does not report the trial’s original sample-size justification or original design assumptions.

The 80% power column gives the planned number of participants per arm for a hypothetical study designed to have an 80% chance of detecting the selected effect under those assumptions, if that effect is present. The 90% power column gives the corresponding planning number for a higher chance of detecting that same selected effect. These are planning illustrations, not observed power.

The rows consider planning for 100%, 75%, and 50% of the observed effect. The values rise as the assumed effect becomes smaller: a smaller difference is harder to distinguish from random variation, so more participants are needed to detect it under the same assumptions. The illustrations use the observed estimate as their starting point, which can be uncertain in a small pilot study. They should not be treated as a recommendation or as a record of the trial’s original design.

The reported figures apply to the primary continuous outcome, and the assumption of equal allocation is a planning choice, distinct from the outcome counts in the trial. The original study enrolled 46 participants, but the registry record does not report whether its enrollment target was based on a formal power calculation or another feasibility objective.

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 = -4.400; pooled standard deviation σ = 9.431.
2. n = 2 × (1.96 + 0.842)² × 9.431² / -4.400² = 72.1, rounded up to 73 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 <- -4.4                      # observed difference in means
sigma <- 9.4314271550926                     # 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(586482)
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 = 73 (80% power), 97 (90% power)
 75% of observed effect: n per arm = 129 (80% power), 172 (90% power)
 50% of observed effect: n per arm = 289 (80% power), 387 (90% power)
power.t.test: 73.1 
Simulated power at n = 73 per arm: 0.802 (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. Analyses Reported by the Sponsor

For the primary outcome, the sponsor reported a two-sided t-test with p = 0.12. The unadjusted recalculation from the posted group summaries gives p = 0.108 and a mean difference of -4.4 parts per million, with a confidence interval from -9.77 to 0.970. These results are broadly similar in direction and interpretation: both p-values are above 0.05, and the interval includes zero.

The recalculation is a simple unadjusted analysis of summary statistics, while the sponsor’s reported test is the trial’s own posted analysis. The registry record does not report enough detail to explain the small difference between the p-values or establish that the two calculations used identical procedures. The sponsor’s result should therefore be distinguished from the recalculated estimate rather than replaced by it.

For the secondary abstinence outcome, the sponsor reported a Fisher Exact p-value of 0.23; the unadjusted recalculation gives p = 0.193. The registry record does not report a discrepancy flag for these results. Neither comparison changes the overall reading: the posted estimates are uncertain, and the intervals for the recalculated comparisons include zero.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when several outcomes, comparisons, or analyses are examined. In general, conducting multiple tests can raise the chance that at least one result appears notable even when there is no underlying difference. A prespecified hierarchy or statistical adjustment can help address that issue, but the registry record does not report whether a multiplicity strategy was planned or applied. The posted primary and secondary p-values should be read as unadjusted results unless a reported analysis states otherwise.

The registry lists five outcome measures and five analyses, while one secondary outcome is posted in the available results. The record does not provide enough detail to determine how the other measures were handled, whether they were prespecified, or whether all planned analyses are represented. It also does not report an interim-analysis plan or whether any interim analyses took place. Neither should be assumed from the registry entry.

Missing-data handling is another important uncertainty. The primary outcome summaries include 22 participants in the nicotine-lozenge arm and 24 in the placebo arm, matching the stated enrollment total of 46. The registry record does not report a participant flow account, outcome completion rates beyond those group counts, reasons for missing observations, or a missing-data method. The secondary outcome also uses the same group counts, but that does not establish that there were no other missing data or exclusions at earlier stages.

The analysis population is not reported in the registry record. It is therefore unclear whether the posted tests were based on all randomized participants, participants with available outcome measurements, or another defined group. The record also does not describe how protocol deviations, treatment adherence, or any crossovers were handled. These omissions limit assessment of potential bias and reproducibility.

In general, a clear analysis plan identifies primary and secondary outcomes, analysis populations, missing-data procedures, multiplicity handling, and any interim analyses. Those details are not reported in the registry record, so conclusions should remain grounded in the posted group summaries and stated tests rather than in assumptions about unreported procedures.

16. 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.

The registry reports zero serious adverse events among 22 participants at risk in the nicotine-lozenge group and zero among 24 participants at risk in the placebo group. It also reports zero other adverse events among 22 and 24 participants at risk, respectively. These are the posted event counts for the groups.

Zero reported events in a small study does not establish that an event cannot occur or that the groups have identical safety profiles. In general, uncommon events may not be observed in a limited number of participants. The registry record does not list serious adverse-event terms, and it does not report death counts for either arm. Death information should therefore be treated as not reported in the registry record, rather than interpreted as zero deaths.

These figures describe adverse-event reporting in this trial; they do not by themselves provide a complete assessment of safety. The registry record does not report further detail about event definitions, collection procedures, or the period over which events were assessed.

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

The results describe a small randomized pilot study of nicotine lozenges used during the night before surgery and up to surgical admission. The nicotine-lozenge group had a lower mean exhaled carbon monoxide concentration than the placebo group, and more participants in that group reported abstinence on the morning of surgery. These are descriptive differences in the posted data.

The uncertainty around both recalculated comparisons is substantial. The primary confidence interval includes zero, as does the secondary risk-difference interval. The sponsor’s reported p-values are 0.12 for the primary comparison and 0.23 for the secondary comparison. These findings do not establish a clear between-group difference, but they also do not show that the groups are equivalent. The estimates remain compatible with a range of possible differences.

The pilot study’s stated goal was to assess feasibility and potential effect size. Its enrollment and imprecise estimates make it more useful as an initial source of information for future planning than as a definitive evaluation. The planning illustrations based on the observed effect are not proof of a particular sample size being sufficient, and the registry record does not report the original sample-size justification.

The data do not answer questions about longer-term abstinence, outcomes after the operation, or effects in populations beyond those enrolled. The registry record does not report the full eligibility criteria or details of missing-data handling and analysis populations. No clinical recommendation follows from these results alone. They are best understood as uncertain estimates from a completed pilot trial focused on a brief preoperative period.

18. Why This Trial Matters Statistically

This trial illustrates several core statistical issues in a compact clinical setting. First, a difference in observed group means does not by itself establish a reliable difference in the wider population. The primary estimate is negative, but its confidence interval includes zero and is broad. Interpreting the estimate together with its precision is more informative than focusing only on the direction of the point estimate.

Second, a pilot study can generate estimates useful for planning while remaining too small to give a precise answer about an outcome. The registry describes feasibility and potential effect size as its goals. The planning illustrations show how the number of participants per arm changes when the assumed effect is reduced, but they do not establish the trial’s original design assumptions or demonstrate observed power.

Third, related outcomes can point in a common descriptive direction without acting as independent confirmation. Exhaled carbon monoxide and self-reported abstinence address the preoperative period through different measurements. Their estimates are both uncertain, and interpretation of the secondary endpoint also depends on how multiple outcomes were planned and handled—details not reported in the registry record.

Finally, a registry entry may leave important analysis details undocumented. Here, the original sample-size justification, missing-data procedures, analysis populations, multiplicity handling, and interim-analysis information are not reported. Recognizing these gaps helps distinguish what the posted results show from what would require additional documentation or a larger, fully specified study.

19. 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 most direct limitation is the small enrollment: 46 participants, with 22 in the nicotine-lozenge arm and 24 in the placebo arm contributing to the primary outcome. The resulting estimates are imprecise, as reflected in the confidence intervals. The trial is described as a pilot, and the registry states that feasibility and potential effect size were goals.

The registry record does not report the original sample-size justification, eligibility criteria in full, participant flow, missing-data procedures, or analysis-population definition. It is therefore not possible from the posted information to assess whether all randomized participants were included in each analysis or why particular outcome counts were used.

The registry also does not report a complete statistical analysis plan, multiplicity handling, or whether interim analyses were performed. Five outcome measures and five analyses are listed, but the available secondary results describe only self-reported abstinence. The unreported measures cannot be treated as null findings.

The nicotine-lozenge description lists 2 or 4 mg and a dosing period beginning at 7 pm before surgery, but the registry’s arm description is incomplete. It does not provide a complete account of dose-selection rules, adherence, or treatment use. The registry also does not report which groups were masked despite listing quadruple masking.

Finally, the outcomes focus on the morning of surgery. The record does not provide longer-term abstinence results or outcomes after surgery. The posted adverse-event figures include no reported events in the listed categories, but death counts are not reported. These limitations constrain both the precision and the scope of interpretation.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Pilot Study: Preoperative Nicotine Lozenges — NCT00586482.
• Registry record last updated 2014-12-22; status last verified 2014-12.
• Results first posted 2014-12-22.
• 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.

23. Record Summary

NCT00586482, titled “Pilot Study: Preoperative Nicotine Lozenges,” was a completed Phase 4 randomized, quadruple-masked, parallel-group study sponsored by Mayo Clinic. The registry lists 46 participants enrolled. The recorded start was 2006-08, and primary completion was 2013-01.

The study compared nicotine lozenges with matching placebo lozenges during the period before surgery. Its primary outcome was mean exhaled carbon monoxide concentration on the morning of surgery; self-reported abstinence was posted as a secondary outcome. The nicotine-lozenge group had a lower observed primary mean and more participants reporting abstinence, but the recalculated confidence intervals include no difference.

The registry describes feasibility and potential effect size as the study’s goals. The original sample-size justification, full analysis plan, missing-data procedures, and analysis populations are not reported in the registry record. The posted estimates are therefore best read as exploratory, uncertain results from a pilot trial.