Crossover Study of Safety and Tolerability of Two Formulations of Adalimumab.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Crossover Study of Safety and Tolerability of Two Formulations of Adalimumab. (NCT01561313), a randomized phase 2 study. The primary outcome is Mean Injection Site Pain on a Visual Analogue Scale (VAS).

2. Clinical Question

3. Trial Design

The registry describes a phase 2, randomized, single-blind, crossover study of two adalimumab formulations in adults with rheumatoid arthritis. The study was completed. The recorded enrollment was 64, and the study ran from 2012-03 to primary completion in 2012-11. The sponsor is listed as AbbVie (prior sponsor, Abbott). The brief summary says the study was conducted in Belgium and the Czech Republic, with three sites in each country.

Both study conditions involved a 40 mg dose of adalimumab in a pre-filled syringe: one using the current formulation and one using the new formulation. In a crossover design, participants receive more than one study condition over time, allowing comparison across conditions in the same trial framework. That general design description does not establish how this study handled the order of formulations, the timing between injections, or possible effects that persist from an earlier dose; those details are not reported in the registry record.

Randomization means the allocation sequence was determined by chance, while single-blind indicates that blinding was used but does not identify who was blinded. The identity of the blinded party is not reported in the registry record. Nor does the record specify the randomization method or give details of concealment. The posted primary outcome observations are listed as 62 for each formulation. Those observations should not be read as a count of unique participants, because the crossover structure allows participants to contribute observations under both conditions.

The primary endpoint was mean injection-site pain immediately after injection. The registry also lists secondary outcomes covering pain at 15 minutes, local skin reactions, and adverse events. The trial design therefore focused on comparing short-term injection experience and recorded safety outcomes, rather than on a stated measure of longer-term rheumatoid arthritis control.

4. Participant Flow and Accounting

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

Before assignment: Two participants, who were randomized to the Current formulation adalimumab/New formulation of adalimumab arm of the study, were excluded from the analysis of injection site-related pain. One participant received one dose of study drug and discontinued because of an adverse event, while the other discontinued before receiving any study drug.

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.

Population: 63 participants received at least one dose of the study drug, and 62 participants were analyzed for injection site-related pain. 63 participants were analyzed for other safety analyses.

6. Primary Endpoint

The registry lists the primary outcome as Mean Injection Site Pain on a Visual Analogue Scale (VAS), measured over Immediately after injection.

The primary endpoint is mean injection-site pain measured immediately after injection using a visual analogue scale in centimeters. The scale runs from 0 to 10 cm: 0 represents no pain and 10 represents the worst possible pain. A participant’s rating is a subjective report of pain, and the group mean describes the average rating among the observations recorded for each formulation.

This outcome is relevant to a formulation comparison because the study’s stated question concerns the experience of receiving an injection. It captures immediate discomfort at the injection site, rather than the underlying activity of rheumatoid arthritis, a change in disease symptoms, or a longer-term clinical outcome. The timing is important: the primary measure is taken immediately after injection, while the registry separately lists a pain measure at 15 minutes post injection.

For the primary comparison, the current formulation had a mean of 3.3 cm and the new formulation had a mean of 1.6 cm. The estimated mean difference, expressed as new formulation minus current formulation, is -1.7 cm. A negative value indicates a lower posted mean rating for the new formulation under that subtraction order. The difference is expressed in the scale’s original units, which makes it interpretable in centimeters rather than only as a standardized statistical quantity.

As a general statistical point, a mean is useful for describing the center of a continuous measure, but it does not show the full distribution of individual ratings. The standard deviations, 2.11 and 2.09 cm, describe the spread of observations around their respective means. The registry record does not give the individual ratings or additional distributional summaries, so the range of experiences among participants cannot be reconstructed from the means alone.

7. Results Posted in the Registry

• New Formulation of Adalimumab: mean 1.60 versus 3.30 on control; difference -1.70 (95% CI -2.44 to -0.96), standardized effect d = -0.81; 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.

Mean Injection Site Pain on a Visual Analogue Scale (VAS)

• 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:
  • New Formulation of Adalimumab: mean 0.90 versus 1.00 on control; difference -0.10 (95% CI -0.66 to 0.46), standardized effect d = -0.06; z-test p = 0.726.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between New Formulation of Adalimumab and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes that cover injection-site pain at a later assessment, local skin findings, and adverse events. The detailed posted secondary results include pain at 15 minutes post injection. The other listed secondary outcomes do not have numeric results reported in the registry record. Consequently, the pattern across the full set of listed secondary outcomes cannot be assessed in detail from the posted record.

The 15-minute pain measure is related to the primary endpoint because it assesses the same general experience at a different time. Its posted means are 1.0 cm for the current formulation and 0.9 cm for the new formulation; the mean difference is -0.1 cm, with a confidence interval from -0.660 to 0.460 and an unadjusted p value of 0.726. Unlike the immediate primary comparison, this interval includes zero. These results describe the later pain assessment and should not be treated as a substitute for the primary endpoint or as evidence about unreported local skin outcomes.

Secondary measures help show whether observations across related outcomes tell a consistent story, but their interpretation depends on how many outcomes were tested and whether the analysis accounted for that testing. Repeatedly testing outcomes increases the chance of finding apparently unusual results even when there is no underlying difference. The registry record does not report a multiplicity procedure, a hierarchy of secondary hypotheses, or detailed analysis methods for the secondary outcomes.

For that reason, unadjusted secondary results carry less weight than a prespecified primary result when many outcomes are examined. This does not make secondary outcomes uninformative; it means they are best treated as supportive or exploratory unless the analysis plan establishes otherwise. The record does not describe such a plan or report analyses for the listed skin-reaction measures, so conclusions about those outcomes are not available from the registry record.

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

• Mean Injection Site Pain on a Visual Analogue Scale (VAS)
• Percentage of Participants With no Hemorrhage/Petechiae in the Draize Scale
• Percentage of Participants With no Erythema in the Draize Scale
• Percentage of Participants With no Edema in the Draize Scale
• Percentage of Participants With no Pruritus in the Draize Scale
• Number of Participants With Adverse Events (AEs)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is continuous: each pain rating is recorded along a visual analogue scale, and the reported summary is a mean with a standard deviation. A mean describes the center of the observed ratings. A standard deviation describes how dispersed individual observations are around that mean. The posted primary means are 3.3 cm and 1.6 cm, with standard deviations of 2.11 and 2.09, respectively. These summaries preserve the original scale units, so the difference is expressed in centimeters.

What does the mean difference represent?

The contrast is defined as the new formulation minus the current formulation. Its estimate is -1.7 cm. A negative estimate means the new-formulation mean is lower under that subtraction order. This is an unadjusted comparison of the posted summary results. It is distinct from a standardized effect size, which expresses a difference relative to variability; the registry also records a standardized effect estimate of -0.809. The centimeter-scale contrast is generally the more direct way to describe the endpoint itself, while a standardized measure can help compare effects measured on different scales.

What does the confidence interval add?

A confidence interval gives a range of estimates compatible with the observed data under the method’s assumptions. The interval for the primary mean difference runs from -2.439 to -0.961 cm. Its placement entirely below zero aligns with the direction of the estimated contrast. The interval communicates uncertainty in the estimate; it does not provide the probability that any particular value in the range is the true effect. The confidence level and the method used to calculate this interval are not reported in the registry record.

A confidence interval is informative alongside a p value because the two convey different aspects of the comparison. The unadjusted p value is <0.001, which describes the compatibility of the observed data with a null hypothesis of no difference under the analysis assumptions. It does not quantify the size of the difference. The estimate gives the observed magnitude, and the interval indicates its statistical precision. Neither alone establishes whether the difference is important to participants.

Why is the crossover structure relevant?

In general, crossover studies observe participants under more than one condition. Comparisons can then take account of the fact that ratings from the same participant may be more alike than ratings from different participants. A suitable analysis may use this pairing, which can improve precision when within-participant variability is lower than variability between participants. This is a general explanation, not a description of the analysis used in this trial. The registry record does not report whether the primary comparison used a paired method, how correlation between observations was handled, or whether the analysis incorporated sequence or period.

Carryover is another general consideration in crossover research: an effect of an earlier condition may remain when a later condition is assessed. Whether carryover is plausible and how it is handled depend on the intervention and study procedures. The interval between doses, sequence details, and any carryover assessment are not reported in the registry record. It is therefore not possible to determine from the posted summary whether these considerations were included in the trial’s analysis.

How should the p value be read?

Under a statistical model and a null hypothesis of no mean difference, the p value measures how compatible the observed result is with that null model. A small p value such as the posted <0.001 indicates low compatibility with the null under the assumptions used. It is not a measure of the probability that chance alone caused the result, nor does it describe the probability that the formulations are equivalent or different in a clinically important way. The p value is unadjusted, and the record does not state whether multiplicity was addressed in the full analysis.

In general, statistical results depend on assumptions about the data and analysis. For continuous ratings, these may include assumptions about the distribution of the outcome or the errors in a model. For a crossover comparison, assumptions also concern repeated measurements and study periods. The registry record does not specify the statistical model, diagnostic checks, transformations, covariate adjustments, or handling of unusual observations. Those details are needed to independently assess whether the chosen method was appropriate.

The posted outcome counts are 62 for each formulation. In a crossover setting, such counts identify observations attached to each condition; they do not on their own indicate unique-participant totals or confirm complete paired records. Enrollment is listed as 64. The registry record does not explain the relationship between enrollment and the observations used, including whether participants withdrew, had incomplete measurements, or were excluded from the analysis.

For interpretation, the key components are the outcome definition, the contrast direction, the estimate, its interval, and the analysis context. The endpoint is immediate self-reported pain; the contrast is new minus current; the estimate is -1.7 cm; the interval is -2.439 to -0.961; and the unadjusted p value is <0.001. The crossover design makes within-participant handling particularly relevant, but the detailed method is not reported in the registry record. Thus, the numerical comparison is clear, while important details for a full methodological appraisal remain unavailable.

11. Confidence Intervals and Precision

The primary mean difference is -1.7 cm, with a confidence interval from -2.439 to -0.961. The interval is entirely below zero, in the same direction as the estimate. This indicates that the posted interval does not include a zero mean difference under the method used to construct it. The unadjusted p value is <0.001, which is consistent with the interval’s direction, although the p value and interval describe different features of the comparison.

The interval is useful because it shows a range of values compatible with the observed data under the analysis assumptions. It also makes clear that the estimate is not known without uncertainty: the observed mean difference is one value, and the interval represents uncertainty around that estimate. The interval’s width should be considered in the context of the 0 to 10 cm scale and the endpoint’s meaning. The registry record does not report a threshold for a clinically important difference, so the interval cannot by itself establish whether all values within it would be important to participants.

The confidence level and the calculation method are not reported in the registry record. That missing information matters when assessing the interval’s formal coverage properties. Likewise, the registry does not explain whether the interval accounts for the crossover structure, paired observations, period effects, or other design features. The posted result is therefore interpretable as a reported interval, but the underlying calculation cannot be fully verified from the record.

The standard deviations of 2.11 and 2.09 cm show that individual ratings varied around the group means. They do not replace the confidence interval for the mean difference: variability among individual observations and uncertainty in a group contrast are related but distinct quantities. Precision is also endpoint-specific. The immediate pain result does not establish the precision of other outcomes or of effects at later times.

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 entries are participants per arm, not total events. They illustrate sample sizes under a stated set of assumptions rather than report the number enrolled or analyzed in this crossover trial. The assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The trial’s own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the illustrative participants per arm for a design that would have an 80% chance of detecting the assumed effect under those planning assumptions, if that effect and model were correct. The 90% power column gives the corresponding planning number for a 90% chance. Greater target power generally requires more participants when the other assumptions are held fixed. These are planning illustrations, not observed power.

The rows use the full observed effect and smaller fractions of that effect. Smaller effects need more participants to detect, all else equal, because they are harder to distinguish from ordinary variability. For example, the planning figures rise when the assumed effect is set to 75% of the observed effect and rise further when it is set to 50%. The values are participants per arm, so they should not be mistaken for total enrollment or for numbers of distinct participants in this crossover study.

The accompanying curve should be read as a visual rendering of the same planning relationship: the required sample size changes as the assumed effect changes. These calculations use a two-arm equal-allocation normal approximation and are not a reconstruction of the trial’s protocol. They do not account for any crossover-specific assumptions unless those are explicitly included, and the registry record does not report the original design calculation.

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 = -1.700; pooled standard deviation σ = 2.100.
2. n = 2 × (1.96 + 0.842)² × 2.100² / -1.700² = 24.0, rounded up to 24 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 <- -1.7                      # observed difference in means
sigma <- 2.10002380938884                     # 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(1561313)
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 = 24 (80% power), 33 (90% power)
 75% of observed effect: n per arm = 43 (80% power), 58 (90% power)
 50% of observed effect: n per arm = 96 (80% power), 129 (90% power)
power.t.test: 25 
Simulated power at n = 24 per arm: 0.787 (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 primary endpoint is clearly identified as mean injection-site pain immediately after injection. The registry also lists multiple secondary outcomes, including pain at 15 minutes, several local skin findings, and adverse events. When a study assesses multiple outcomes or makes multiple comparisons, the chance of at least one apparently unusual result can increase. A statistical plan may address this through a prespecified testing hierarchy or an adjustment for multiplicity, but whether either approach was used is not reported in the registry record.

The primary comparison is presented with an unadjusted p value of <0.001. The registry record does not state whether that value is the result of the sponsor’s primary analysis or whether it reflects an adjustment for the crossover structure. It also does not give a multiplicity adjustment. The record lists no reported analyses for secondary outcomes, even though outcome measures are listed. Thus, the posted information does not establish how secondary hypotheses were tested or whether any were formally confirmatory.

Missing-data handling is also not reported in the registry record. The listed enrollment is 64, while the primary outcome has 62 observations associated with each formulation. These figures do not establish how many participants contributed complete paired observations, why any measurements may be absent, or whether missing values were imputed. The registry does not describe withdrawals, exclusions, or sensitivity analyses for missing outcomes.

The analysis population is not reported in the registry record. It is not stated whether analyses included all randomized participants, only participants who received both formulations, or another defined group. Nor does the record explain how protocol deviations or incomplete crossover sequences were handled. These omissions matter because the analysis population and missing-data approach can affect the estimate and its uncertainty.

The study is described as randomized, single-blind, and crossover, but details needed to assess the implementation are limited. The randomization procedure, identity of the blinded party, sequence allocation, period effects, and carryover assessment are not reported in the registry record. Without these details and the statistical analysis plan, the posted numerical results can be described, but the full prespecification and robustness of the analyses cannot be evaluated.

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’s serious adverse event figures show zero affected participants in the serious-event category for both formulation groups. The at-risk counts listed are 63 for the current formulation and 62 for the new formulation. The figures describe participants recorded as having serious adverse events; they are not the number of individual serious-event reports. The registry does not list serious adverse event terms in the posted record.

For other adverse events, the registry records 2 affected participants with the current formulation among 63 at risk, and 1 affected participant with the new formulation among 62 at risk. These counts are descriptive and should be interpreted in the context of the study’s size and crossover design. The record does not provide event types, severity details, timing, relationship to treatment, or a statistical comparison for these figures.

Death counts are not reported in the registry record. The safety figures alone do not establish that the formulations have equivalent safety profiles or that uncommon events could be ruled out. They describe the adverse event information recorded for this study, with important detail and analysis methods not available in the registry record.

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

The posted primary result is a lower mean immediate pain rating for the new formulation than for the current formulation. The means are 1.6 cm and 3.3 cm, respectively, and the mean difference, new minus current, is -1.7 cm. Its confidence interval is -2.439 to -0.961, and the unadjusted p value is <0.001. These figures describe the pain ratings recorded in this randomized, single-blind crossover study.

The result does not, by itself, show that the formulations differ in rheumatoid arthritis disease control, long-term health outcomes, or overall treatment benefit. The primary endpoint is immediate self-reported injection-site pain. It also does not establish the importance of the difference to participants, because no clinically important threshold is reported in the registry record. Statistical evidence about a mean difference and evidence about practical importance are related but are not the same question.

The later pain assessment has a smaller posted mean contrast, with a confidence interval that includes zero and an unadjusted p value of 0.726. That later result concerns a different assessment time and should be interpreted on its own terms. Other listed secondary outcomes do not have numeric results reported in the registry record, so their findings cannot be inferred from the primary result.

The crossover format may support comparisons across formulations within participants, but the analysis details needed to assess that feature are not reported. The registry record does not describe the statistical model, handling of repeated measurements, missing data, or the analysis population. It also does not report the confidence-interval method or a multiplicity plan. Those uncertainties limit how completely the result can be evaluated.

The safety information records no serious adverse event participants in either formulation group and a small number of participants with other adverse events. The available details do not establish comparative safety beyond those recorded counts. The study’s posted findings therefore speak to a specific short-term pain measure and descriptive safety information; they do not settle broader clinical questions.

17. Why This Trial Matters Statistically

This trial is statistically notable because its design and endpoint require attention to the structure of the data. A crossover study exposes participants to more than one formulation, so the comparison may involve repeated observations from the same people. A statistical analysis that accounts for within-participant correlation can differ from one that treats all observations as independent. The registry record identifies the crossover design but does not report the analysis method, making that distinction important when interpreting the estimate.

The primary outcome is a continuous, participant-reported rating with a clear scale and time point. Reporting a mean difference in centimeters makes the contrast directly interpretable in the endpoint’s units. The confidence interval and p value provide complementary information: the interval gives a range of estimates under the method’s assumptions, while the p value summarizes compatibility with a null hypothesis. Neither replaces consideration of clinical importance, which is not quantified in the record.

The difference between the immediate and 15-minute pain results also illustrates why timing is part of endpoint definition. A single label such as injection-site pain can refer to distinct measurements at distinct times, and results at one time should not be assumed to apply at another. The registry lists additional local-reaction and safety outcomes, but detailed numeric results are not available for all of them.

Finally, the planning illustrations show how required sample size depends on the effect one aims to detect and the chosen power target. They are not the trial’s original design calculation, which is not reported in the registry record. Separating planning assumptions from observed trial results helps avoid treating an illustrative sample-size exercise as evidence about the study’s achieved power or design rationale.

18. Limitations

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

The registry record leaves several trial-specific details unavailable. It does not report the sequence of formulation exposure, the interval between injections, or how periods were defined. These details are pertinent to a crossover study because order and effects persisting across periods may influence comparisons. The record also does not identify who was blinded or provide the randomization procedure.

The posted primary means and observation counts do not show the individual participant data or clarify how many participants contributed paired measurements. Enrollment is listed as 64, while 62 observations are listed for each formulation. The registry does not explain the difference, report the number of completed sequences, or describe missing-data handling and exclusions. It also does not define the analysis population.

Statistical methods are incompletely described. The model used for the primary comparison, treatment of within-participant correlation, adjustment for sequence or period, and checks for carryover are not reported in the registry record. The confidence-interval method and confidence level are also not reported. These gaps prevent a full independent appraisal of the assumptions behind the estimate and interval.

The endpoint is an immediate subjective pain rating, so it captures a specific aspect of injection experience rather than a broad clinical outcome. The record does not report a threshold for clinical importance. Although secondary measures are listed, detailed numeric results are not reported for the listed local skin outcomes, and no secondary analyses are reported in the registry record. Multiplicity handling is also not reported.

The safety data are limited to affected-participant counts and at-risk counts. Event descriptions, severity, timing, relatedness, and a formal comparative analysis are not given. Death counts are not reported in the registry record. These limitations mean the posted information is most useful for describing the stated short-term endpoint and recorded event counts, rather than drawing broad conclusions beyond them.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Crossover Study of Safety and Tolerability of Two Formulations of Adalimumab. — NCT01561313.
• Registry record last updated 2014-02-20; status last verified 2014-01.
• Results first posted 2014-02-20.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

This completed phase 2 study was randomized, single-blind, and crossover, and compared current and new formulations of adalimumab in adults with rheumatoid arthritis. The primary endpoint was mean injection-site pain immediately after injection on a 0 to 10 cm visual analogue scale. Posted means were 3.3 cm for the current formulation and 1.6 cm for the new formulation. The estimated difference was -1.7 cm, with a confidence interval from -2.439 to -0.961 and an unadjusted p value of <0.001.

The registry also lists pain at 15 minutes, local skin findings, and adverse events. Numeric results are available for the 15-minute pain measure and adverse-event counts, while other listed outcomes do not have numeric results reported in the registry record. Important details about crossover analysis, missing data, analysis populations, and multiplicity are not reported, so the findings should be interpreted as specific to the posted outcomes and methods information.