Evaluating the Safety and Efficacy of Fractionated Carbon Dioxide Therapy in Postoperative Lower Extremity Wound Healing: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluating the Safety and Efficacy of Fractionated Carbon Dioxide Therapy in Postoperative Lower Extremity Wound Healing (NCT03644849), a randomized na study. The primary outcome is Number of Participants With Completely Healed Lower Extremity Wounds.

2. Clinical Question

The clinical question is about a specific postoperative setting rather than wound healing in every population or circumstance. The registry summary describes follow-up visits immediately after treatment and at 4, 8, and 12 weeks after surgery. At those visits, wound size, photographs, and wound temperature were to be collected; participants were also given a diary for wound-related adverse events. The results posted for the primary outcome concern complete healing by week 12. They do not, on their own, describe the rate or timing of healing at every visit, or establish how the results might apply beyond the eligible population in this single-center study.

3. Trial Design

The registry describes a single-center, prospective, double-blinded, randomized, placebo-controlled trial with a parallel-group design. It lists the study as completed, with enrollment of 48. The recorded start date is 2018-09-28 and the primary completion date is 2020-11-19. The sponsor is St. Louis University, and the phase is recorded as not applicable.

Participants were assigned to a single immediate postoperative treatment with ablative fractional carbon dioxide laser therapy or to sham laser treatment. The named device was CO2RE®. The registry summary says the laser group received one treatment after surgery; the sham group was described as undergoing a sham treatment. Further details of the sham procedure are not reported in the registry record. Although double blinding is recorded, which study roles were masked and how masking was maintained are not reported.

The planned follow-up described in the registry included a visit immediately after therapy and visits at 4, 8, and 12 weeks after surgery. The summary identifies wound size, photographs, wound temperature, and diary-recorded wound-related adverse events as collected information. The primary endpoint was assessed at 12 weeks. The posted primary outcome counts are based on 23 participants in the laser group and 21 in the sham group. The registry’s overall enrollment figure is 48; reasons why the primary outcome counts differ from that enrollment figure are not reported.

The record describes a randomized comparison, but it does not report the original sample-size justification, the allocation-generation or concealment procedures, or the detailed statistical analysis plan. Those omissions limit what can be said about the conduct and prespecification of the analysis. They do not change the basic design distinction: the posted comparison is between participants assigned to laser treatment and participants assigned to a sham treatment.

4. Participant Flow and Accounting

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

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Completely Healed Lower Extremity Wounds, measured over 12 weeks (enrollment time per subject).

The primary endpoint counts participants whose lower-extremity wound was completely healed by the end of the study at week 12. The registry defines complete healing as reepithelization of the wound. This is a binary outcome: each participant is counted according to whether the wound met that definition at the specified assessment point.

In general, a binary endpoint can provide a direct summary of how many participants reached a prespecified clinical state. It is often easier to interpret than a continuous measurement when the question concerns whether a particular event or condition occurred. The count does not, however, describe the degree of healing among wounds that did not meet the complete-healing definition, nor does a single end-of-study assessment describe exactly when healing occurred. Those questions would require other reported measures or analyses.

For this trial, the endpoint focuses on complete healing after lower-extremity surgery and gives a clear outcome for comparing the randomized groups at 12 weeks. The registry’s outcome description does not state who assessed reepithelization, whether assessors used a standardized adjudication process, or how participants without a week-12 assessment were handled. Those details are not reported in the registry record.

7. Results Posted in the Registry

• Fractional Carbon Dioxide Laser Intervention Group: 87.0% (20/23) versus 85.7% (18/21) on control; risk difference 1.2 percentage points (95% CI -19.1 to 21.6), risk ratio 1.01 (0.80–1.28); unadjusted two-proportion z-test p = 0.905.

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.

Quality of Life Measure EQ-5D-5L

• 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:
  • Fractional Carbon Dioxide Laser Intervention Group: mean 90.70 versus 87.50 on control; difference 3.20 (95% CI -2.83 to 9.23), standardized effect d = 0.31; z-test p = 0.298.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Fractional Carbon Dioxide Laser Intervention Group and the control. The interval gives the range of effects that remain compatible with the data.

Wound Temperature Associated With Carbon Dioxide Ablative Fractional Laser for Healing Postoperative Lower Extremity Wounds.

• 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:
  • Fractional Carbon Dioxide Laser Intervention Group: mean 32.41 versus 31.76 on control; difference 0.65 (95% CI -0.68 to 1.98), standardized effect d = 0.29; z-test p = 0.338.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Fractional Carbon Dioxide Laser Intervention Group and the control. The interval gives the range of effects that remain compatible with the data.

The two posted secondary outcomes cover different aspects of the postoperative course: EQ-5D-5L quality-of-life scores and wound temperature. At the level of the group averages, both comparisons point toward higher values in the laser group. Their confidence intervals include no difference, and the unadjusted comparisons do not provide clear evidence of a group contrast. They therefore offer no precise confirmation of the primary outcome pattern.

These measures relate to, but do not duplicate, the primary endpoint. Complete reepithelization is a categorical healing status at week 12, while quality-of-life scores and wound temperature are continuous measurements. A group difference in a secondary measure would not by itself establish a difference in complete healing; similarly, a primary endpoint result does not determine how the secondary measures should behave. The registry gives the secondary outcome time frame as 12 weeks per participant, but does not report analyses across the scheduled visits.

Unadjusted secondary results generally carry less weight when multiple outcomes or comparisons are considered because each additional test creates more opportunity for chance findings. In general, a prespecified multiplicity strategy can help control how such results are interpreted. No multiplicity adjustment or hierarchical testing plan is reported in the registry record. The reported secondary summaries should therefore be treated as exploratory descriptive evidence rather than independent confirmation of a treatment effect. The record also lists four outcome measures overall but posts two secondary outcomes; details about the other measures and any associated analyses are not reported.

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

• Quality of Life Measure EQ-5D-5L
• Wound Temperature Associated With Carbon Dioxide Ablative Fractional Laser for Healing Postoperative Lower Extremity Wounds.

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary because it records whether each participant’s wound was completely healed by week 12. The posted arm summaries give the number of participants meeting the endpoint and the number included in that summary. A comparison of proportions can be expressed on several scales, such as a risk difference, risk ratio, or odds ratio. Each scale answers a related but not identical question, so the scale and its interval should be read together rather than treating one number as a complete description.

What does a risk difference describe?

In general, a risk difference subtracts the event proportion in one group from the event proportion in the comparison group, with the direction determined by which group is placed first. A value near zero indicates similar observed proportions on that scale; a positive or negative value indicates the direction of the observed contrast under the stated ordering. The registry-based comparison reports a slightly positive point estimate for the laser group relative to sham. Its confidence interval crosses zero, meaning that the summary data are compatible with a contrast in either direction as well as no difference.

Risk ratios and odds ratios describe the same binary outcome on relative scales. In general, a relative estimate of one is the no-difference value for those scales, while a risk difference uses zero as its no-difference value. These scales can appear numerically different without contradicting one another. The primary interpretation should remain tied to the actual endpoint and its event counts, rather than treating any one relative measure as decisive.

What does the p-value add?

The posted primary comparison includes an unadjusted p-value of 0.905. In general, a p-value is calculated under a null hypothesis and a specified statistical model. It describes how compatible the data are with that null model; it is not a measure of clinical importance, the chance that the null hypothesis is true, or a probability that the result will repeat. An unadjusted value does not account for testing multiple outcomes or comparisons. The registry does not report the trial’s own analysis plan or a sponsor-reported statistical analysis, so the displayed p-value should be understood as an unadjusted summary-based calculation, not as evidence of a documented prespecified procedure.

How should continuous secondary measures be read?

The quality-of-life and wound-temperature outcomes are reported as means with standard deviations. In general, a mean describes the center of a set of measurements, while a standard deviation describes their spread among participants. The mean difference contrasts the group averages. For EQ-5D-5L, the posted means are 90.7 with a standard deviation of 10.4 in the laser group and 87.5 with a standard deviation of 10.0 in the sham group. The estimated mean difference is 3.2, with a confidence interval from -2.83 to 9.23 and an unadjusted p-value of 0.298.

For wound temperature, the posted means are 32.41 degrees Celsius with a standard deviation of 2.51 in the laser group and 31.76 degrees Celsius with a standard deviation of 1.98 in the sham group. The estimated mean difference is 0.65 degrees Celsius, and the interval includes zero; the unadjusted p-value is 0.338. The registry does not report analyses of repeated measurements across the scheduled visits, so these endpoint summaries should not be taken as evidence of a trajectory over time.

What is not established by these calculations?

General statistical methods can adjust for baseline variables, repeated measurements, clustering, or other features when they are relevant and specified. The registry record does not report an adjusted analysis, the exact test used for each posted comparison, or the detailed model assumptions. The planning illustrations use a normal approximation, but that stated planning assumption should not be mistaken for confirmation of the method used in an original trial analysis. No interim analyses, stopping rules, or sample-size justification for the trial are reported. The posted calculations therefore support a limited reading of the summarized outcomes, not reconstruction of the full analysis plan.

11. Confidence Intervals and Precision

A confidence interval expresses uncertainty around an estimated group contrast under the assumptions of the calculation. In general, a narrower interval indicates greater precision, while a wider interval leaves a broader range of values compatible with the data. An interval is not a guarantee that the true effect lies within its bounds, and it does not show the probability that a particular effect is correct.

For the primary risk difference, the posted interval includes zero and extends to both negative and positive values. This means the observed counts do not rule out either direction of the group difference or no difference. The point estimate is close to the no-difference value, but the interval is broad relative to that point estimate. The primary p-value of 0.905 is consistent with the interval’s lack of clear separation from the null value; it should not be read as proof of equivalence.

The secondary mean-difference intervals also include zero. For EQ-5D-5L, the interval runs from -2.83 to 9.23 around the estimated mean difference of 3.2. For wound temperature, the interval includes zero around the estimated mean difference of 0.65 degrees Celsius. These intervals likewise leave uncertainty about the direction and size of the group contrasts.

Precision is shaped by the amount and variability of the observed information, but the registry does not report a trial-specific precision target. The primary endpoint summaries include 23 participants in the laser group and 21 in the sham group, while enrollment is recorded as 48. Reasons for the difference between enrollment and outcome-summary counts are not reported. Without details about missing outcomes or analysis populations, it is not possible to determine whether those counts reflect exclusions, unavailable assessments, or another reason. The uncertainty should therefore be interpreted alongside the incomplete reporting about who contributed to each analysis.

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 sample-size illustrations are planning examples, not a report of the trial’s original design assumptions. For the binary primary outcome, the displayed figures are participants per arm. The stated planning 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 set to the stated fraction of the observed effect. The trial’s own sample-size justification is not reported in the registry record.

The 80% power column gives the number of participants per arm that the planning calculation estimates would be needed to have an 80% chance of detecting the specified effect, under those assumptions, if that effect were the true one. The 90% power column gives the corresponding planning number for a 90% chance. These are not guarantees: power depends on the assumed effect, analysis, and other design conditions. Smaller effects require more participants because they are harder to distinguish from random variation.

For the primary endpoint, planning for 100% of the observed effect gives 12,000 participants per arm for 80% power and 16,064 for 90% power. Planning for 75% of the observed effect gives 21,538 and 28,833 participants per arm, respectively. Planning for 50% gives 48,917 and 65,486 participants per arm. The large planning figures reflect the small observed difference used as the basis for these illustrations; they are not a statement about what the original investigators planned.

The sample-size display and its curve describe how the planning estimate changes as the target effect becomes smaller or the requested power increases. The figures are not observed power, and they do not determine whether the trial was well designed. For the continuous secondary outcomes, the stated convention is also participants per arm; only time-to-event displays would use total events, and no time-to-event outcome is reported for this study.

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

Worked calculation for this trial

1. Control proportion p₀ = 0.857; treatment proportion p₁ = 0.870; average p̄ = 0.863.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4857 = 0.9520.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4857 = 0.4087.
4. n = (0.9520 + 0.4087)² / (0.0124)² = 11,999.8, rounded up to 12,000 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 <- 0.857142857142857                          # control proportion
p1 <- 0.869565217391304                          # 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(3644849)
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 = 12,000 (80% power), 16,064 (90% power)
 75% of observed effect: n per arm = 21,538 (80% power), 28,833 (90% power)
 50% of observed effect: n per arm = 48,917 (80% power), 65,486 (90% power)
power.prop.test: 11999.8 
Simulated power at n = 12,000 per arm: 0.803 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity plan, such as an adjustment for testing multiple outcomes or a rule establishing which comparisons take priority. This matters because the study includes a primary endpoint and secondary outcomes, and the summary describes several measurements during follow-up. In general, interpreting several unadjusted tests as if each were the sole planned test can overstate the strength of evidence. The posted secondary comparisons are unadjusted, and no analysis accounting for multiple testing is reported.

Missing-data handling is also not reported. The primary outcome counts use 23 participants in the laser group and 21 in the sham group, while enrollment is recorded as 48. The adverse-event summaries list 24 participants at risk in each group. These different denominators are part of the registry record, but the reasons for them are not stated. They should not be attributed to loss to follow-up, exclusions, or any other specific cause without further information.

The registry does not report whether the primary analysis used an intention-to-treat population, a per-protocol population, or another definition. The population field for the primary endpoint is blank. There is no reported description of how unavailable week-12 wound assessments were handled, whether imputation was used, or whether sensitivity analyses were conducted. These omissions make it difficult to assess how robust the results are to missing outcomes.

The record reports zero analyses, and no detailed statistical analysis plan, interim-analysis procedure, stopping rule, or outcome-adjudication process is reported. It is therefore not possible to establish from the registry whether the posted analyses were prespecified or to reconstruct their full methods. This is a reporting limitation, not evidence that a particular procedure was or was not performed.

15. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The adverse-event summary lists 24 participants at risk in each group. It records zero participants with a serious adverse event in the fractional carbon dioxide laser group and zero in the sham group. Deaths are recorded as zero in both groups. The summary lists other, non-serious adverse events for 4 participants in the laser group and 2 participants in the sham group.

These are counts as posted, not a complete characterization of the nature, timing, severity, or cause of every event. No serious adverse-event terms are listed. The registry does not report event relatedness, the method or duration of safety surveillance, or whether all participants contributed equally to adverse-event reporting. A recorded count of zero serious events does not establish that the risk is absent; it describes what is recorded for the study groups. The other-event counts should also be read as descriptive, without inferring that treatment caused or prevented those events.

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

The registry results show that complete healing by week 12 was recorded for 20 of 23 participants assigned to fractional carbon dioxide laser treatment and 18 of 21 assigned to sham treatment. The estimated unadjusted difference is slightly in the direction of more healing in the laser group, but the confidence interval includes no difference and values on either side of it. The posted comparison therefore gives an imprecise estimate rather than a clear separation between groups.

This is not evidence that the groups are equivalent. Equivalence requires a prespecified margin and an analysis designed to assess whether the uncertainty is sufficiently narrow to exclude differences larger than that margin. Such a margin and analysis are not reported in the registry record. Nor does a large p-value establish that an effect is absent. It indicates that the posted data, analyzed in this unadjusted comparison, do not provide a clear distinction from the no-difference value.

The findings are specific to the adults eligible for this single-center study, the immediate postoperative treatment described, the sham comparison, and the 12-week primary assessment. The registry summary excludes people with certain health conditions, and it does not establish how results would apply to excluded groups or other kinds of wounds. The posted endpoint also gives healing status at one time point rather than the full course of wound healing.

The secondary measures and safety counts add context but do not settle the uncertainty in the primary comparison. The secondary comparisons are unadjusted, and the record does not report a multiplicity strategy or detailed analysis methods. Safety counts are descriptive and do not include event relatedness or full surveillance details. In general, a registry result should be interpreted in light of its design, outcome definitions, precision, and reporting completeness. Here, those considerations support a cautious, limited description of the observed results rather than a broad conclusion about efficacy or safety.

17. Why This Trial Matters Statistically

This trial illustrates why the size of an observed difference and the precision of its estimate need to be considered together. The primary outcome counts are close in the two groups, and the unadjusted point estimate is near the no-difference value. The confidence interval nevertheless spans both directions, so the evidence does not tightly determine the size or direction of the underlying contrast. A point estimate alone would conceal that uncertainty.

The planning illustrations also show how strongly sample-size requirements can depend on the effect selected for detection. They are based on the observed effect, use equal allocation and a normal approximation, and show larger requirements as the target effect is reduced or the desired power is increased. These figures are useful for understanding a planning relationship, but they are not the trial’s original justification and are not a retrospective measure of whether the trial had enough power.

The record is also a reminder that registry summaries do not always provide the detail needed to reconstruct an analysis. Enrollment, primary outcome counts, and adverse-event denominators are recorded, but the reasons for their differences are not. The analysis population, missing-data handling, multiplicity approach, and detailed statistical plan are not reported. Those details affect how confidently results can be interpreted and reproduced.

For biostatistical interpretation, the central lesson is to keep the randomized comparison, endpoint definition, uncertainty interval, and reporting limitations in view at the same time. The observed counts are informative about this study’s participants, but the broad uncertainty and incomplete analysis reporting constrain stronger conclusions.

18. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The study is described as single-center, and enrollment was 48. That setting and eligibility criteria limit how far the results can be generalized. The registry summary excludes adults with poor immune systems, current pregnancies, uncontrolled diabetes, or lower-extremity venous or arterial disease; the results do not directly describe those excluded groups. The intervention was a single treatment immediately after surgery, and the primary outcome was assessed at 12 weeks, so the record does not establish longer-term outcomes or effects of different treatment schedules.

The primary outcome counts are based on 23 participants in the laser group and 21 in the sham group, while the enrollment figure is 48. Adverse-event summaries use 24 participants at risk in each group. The registry does not explain these denominator differences or report the analysis population and missing-outcome procedures. This makes it difficult to determine how complete the outcome data were or how the analysis population relates to randomized enrollment.

Although the study is recorded as double-blinded, the registry does not identify which roles were masked or describe the sham procedure in detail. It also does not report how complete healing was assessed, whether assessment was independently adjudicated, or whether outcome assessors remained masked. The original sample-size justification, statistical analysis plan, multiplicity strategy, and interim-analysis details are not reported. The posted comparisons are unadjusted, and no analyses are reported in the registry record. These limitations concern the detail available for interpretation; they do not establish that any particular method was used or omitted during the conduct of the study.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Evaluating the Safety and Efficacy of Fractionated Carbon Dioxide Therapy in Postoperative Lower Extremity Wound Healing — NCT03644849.
• Registry record last updated 2022-01-11; status last verified 2021-12.
• Results first posted 2022-01-11.
• 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

The registry record describes a completed, single-center, prospective, double-blinded, randomized, sham-controlled, parallel-group trial of one immediate postoperative fractional carbon dioxide laser treatment for lower-extremity wounds after Mohs surgery. Enrollment is recorded as 48. The primary outcome was the number of participants with a completely healed wound at 12 weeks, defined as reepithelization.

Complete healing was recorded for 20 of 23 participants in the laser group and 18 of 21 in the sham group. The unadjusted comparison has a confidence interval that includes no difference and a p-value of 0.905. The registry also posts EQ-5D-5L and wound-temperature outcomes, without reported analyses. Serious adverse events and deaths are recorded as zero in both groups; other adverse events are listed for 4 laser-group participants and 2 sham-group participants.

The registry does not report the trial’s original sample-size justification, detailed analysis plan, analysis population, missing-data procedures, or multiplicity strategy. These gaps limit interpretation of the posted summaries.