Safety & Tolerability Study That Compares Restylane to Restylane With Lidocaine While Correcting Wrinkles in the Nasolabial Folds: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety & Tolerability Study That Compares Restylane to Restylane With Lidocaine While Correcting Wrinkles in the Nasolabial Folds (NCT00797459), a randomized na study. The primary outcome is Treatment Difference in Pain as Measured by a Visual Analogue Scale.

2. Clinical Question

The clinical question is a within-participant comparison: each participant received both products, one on each side of the face. This design focuses the primary comparison on the difference in reported pain between sides for the same person, rather than a comparison between two separate groups of participants. The outcome description defines 0 mm as no pain and 100 mm as the worst pain. A lower score therefore represents less pain on that scale, while the difference between the two side-specific scores expresses the contrast of interest.

The registry also lists wrinkle improvement at Day 14 as a secondary outcome. That outcome concerns the number of participants with improvement compared with baseline, rather than the immediate pain score. The pain and improvement measures address different aspects of the treatment experience and are interpreted separately. The record does not report a broader clinical question or additional primary outcomes.

3. Trial Design

This was a randomized, double-blind study with a split-face design. A total of 60 participants received both injectable gels once: Restylane on one side of the face and Restylane-L on the other. Participants were blinded to which side received which product. The record does not describe the method used to generate the random allocation or give further details about who else was masked.

The split-face structure is important to the interpretation. Each participant contributes information under both products, so the two side-specific observations are linked within a person. Individual characteristics shared by both sides are thereby held constant for the comparison, although side-specific features and measurement variability can still matter. The record identifies the study model as single group, which is consistent with one group of participants receiving both products rather than separate product-specific groups.

The planned enrollment was 60, and the posted primary outcome includes 60 observations for each product side. Enrollment and treatment occurred within a short registry-recorded period: the study started in 2008-11, primary completion was 2009-01, and status is completed. The phase is listed as NA. The registry describes the intervention as a device and names the products as Restylane and Restylane-L.

The primary outcome was treatment difference in pain measured on a visual analogue scale after injection on the treatment day. Wrinkle improvement at Day 14 was listed as a secondary outcome. The registry record does not report the original sample-size justification, the intended statistical analysis plan, details of the randomization procedure, or a fuller description of the analysis population. Those omissions limit how fully the reported summary can be matched to the original protocol.

4. Participant Flow and Accounting

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

Overall Study

Analysis population for the primary outcome, as defined in the registry: This is a split-face design. Restylane and Restylane with Lidocaine was injected to different sides of the subject's face. A total of 60 subjects received both products. The study evaluated which side of the face had less pain, as measured by the Visual Analogue Scale (VAS).

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 Treatment Difference in Pain as Measured by a Visual Analogue Scale, measured over After Injection on Day of Treatment.

The primary endpoint measures pain following injection on the treatment day using a visual analogue scale. The scale is described as running from 0 mm, meaning no pain, to 100 mm, meaning the worst pain. The posted results summarize the score for each product side with a mean and standard deviation, then report a mean difference for Restylane-L relative to Restylane.

A pain scale is useful for this question because pain is a subjective experience that can be recorded by the person receiving treatment. In general, a continuous score preserves more gradation than a simple yes-or-no response: it can distinguish among different reported levels of pain rather than only indicating whether pain was present. A mean summarizes the average score across observations, while the standard deviation describes how dispersed individual scores are around that average.

In this study, each participant had an observation for both sides of the face. The clinically relevant statistical contrast is therefore the difference in pain scores between the two products within participants. The registry reports side-specific means and standard deviations and a mean-difference estimate. The registry record does not explain the precise analysis method used to account for the paired observations, so the displayed group summaries alone should not be treated as a complete description of that method.

The endpoint is narrowly timed to immediately after injection on the treatment day. It does not, by itself, describe pain at later times or other aspects of tolerability. The separate Day 14 wrinkle-improvement outcome addresses a different question.

7. Results Posted in the Registry

• Restylane-L: mean 14.70 versus 44.90 on control; difference -30.20 (95% CI -39.34 to -21.06), standardized effect d = -1.18; 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.

Wrinkle Improvement at Day 14

• 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:
  • Restylane Side of Face: 98.3% (59/60) versus 100.0% (60/60) on control; risk difference -1.7 percentage points (95% CI -4.9 to 1.6), risk ratio 0.98 (0.95–1.02); unadjusted two-proportion z-test p = 0.315.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Restylane Side of Face and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists one secondary outcome: wrinkle improvement at Day 14 compared with baseline. Its counts show improvement recorded on both product sides for nearly all participants. The posted risk-difference estimate is close to no difference, and its confidence interval includes no difference; the unadjusted p-value does not indicate a clear separation between the sides. These findings contrast with the primary pain result, which is a treatment-day score and has a posted interval below zero.

The outcomes address different questions and should not be combined into a single conclusion. Pain was recorded after injection on the treatment day, while wrinkle improvement was assessed at Day 14. The secondary endpoint is a participant count, whereas the primary endpoint is a continuous score. A similar pattern across those outcomes is not required: one product contrast may differ by outcome, and a result for one endpoint cannot substitute for evidence about another.

Secondary results generally carry less confirmatory weight when the statistical plan, outcome hierarchy, and multiplicity handling are not described. If many outcomes or comparisons are examined, the chance of at least one apparently notable finding can rise. The registry record does not report a multiplicity adjustment or a formal analysis entry for the secondary endpoint. Its result is therefore best treated as supportive descriptive information, not as an independent confirmation of the primary finding.

There is only one secondary outcome posted in the record, so a broad pattern across multiple secondary endpoints cannot be assessed. The record also does not report further details about how improvement was defined or evaluated. Interpretation should stay with the endpoint as registered and avoid assuming a threshold, assessor method, or analysis that is not documented.

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

• Wrinkle Improvement at Day 14

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each side receives a numerical pain score on the visual analogue scale. The registry summarizes each side with a mean and standard deviation. The mean gives the arithmetic average of the recorded scores. The standard deviation describes variation among observations around that average; a larger standard deviation indicates more spread, not greater uncertainty in the mean by itself.

The posted mean-difference estimate is expressed as Restylane-L relative to Restylane. Its negative direction means the Restylane-L average is lower. A contrast is more informative than looking only at two separate means because it directly addresses the question about difference. Still, the two product observations come from the same participants. In a split-face study, the statistical analysis ideally reflects that dependence. The registry record does not report the precise method used to account for pairing, so the method cannot be verified from the summaries alone.

What does a confidence interval communicate?

In general, a confidence interval combines an estimate with a measure of its statistical uncertainty. A relatively narrow interval indicates more precision in the estimate under the model used; a wider interval indicates less precision. The interval is not a description of the spread of individual participants’ scores—that is what the standard deviations help describe. Nor does an interval guarantee that the true effect lies within its limits. Its interpretation depends on the analysis method and assumptions.

The posted primary confidence interval runs from -39.34 to -21.06 around the mean difference of -30.2. The registry record does not identify the confidence level or give enough detail to reconstruct the interval’s method. It is therefore appropriate to describe the interval’s location and its uncertainty without attributing an unstated confidence level or claiming a particular paired-data procedure.

How should the p-value be understood?

In general, a p-value measures how compatible the observed data are with a specified null model, assuming the test’s assumptions hold. The primary unadjusted p-value is <0.001. This is evidence against a zero-difference null under the test used, but it is not a measure of effect size, a probability that the result will replicate, or proof that all participants experienced the same difference. The registry record does not identify the test, its assumptions, or any adjustment for multiple comparisons.

“Unadjusted” indicates that the p-value is not reported as adjusted for a multiplicity procedure. That matters when several outcomes or comparisons are examined: repeated testing can increase the chance of finding a small p-value even when there is no true effect. The record lists a secondary outcome but does not report a multiplicity strategy. The primary outcome remains the designated main result in the registry, but the analysis plan and hierarchy are not fully described.

Why is the split-face structure relevant?

General statistical reasoning distinguishes paired observations from independent observations. In paired data, the outcome on one side is linked to the outcome on the other side because both belong to the same person. A paired analysis uses the within-person differences and their variability. Treating the two sides as unrelated can fail to reflect that linkage. The registry’s side-specific sample counts and summaries do not reveal the distribution of within-person differences, which is needed to fully assess a paired analysis from aggregate information alone.

The posted mean difference is consistent with subtracting the two side-specific means, but the variability of paired differences cannot be recovered from those means and standard deviations alone. No new paired standard error or test statistic should be inferred from the available summaries. The registry record does not report a full analysis entry, and the stated comparison does not identify whether the estimate or its uncertainty came from a paired procedure.

What do the planning illustrations represent?

The sample-size figures are planning illustrations based on fractions of the observed effect. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They are not the original study’s stated design calculations, and the record does not report the assumptions used when the trial was planned. The split-face design also means that an illustration based on equal allocation between arms should not be confused with a description of the actual participant allocation.

In general, over-dispersion means that observed variability is greater than a model assumes. If a planning calculation understates variability, it can overstate how much precision or power a proposed sample size would achieve. The registry record does not provide information to assess over-dispersion or to confirm whether the normal approximation fits the planning illustration. More broadly, planning calculations depend on assumptions about the effect to detect, variability, allocation, and analysis method; changing those assumptions can change the required sample size.

The registry outcome summaries are descriptive information, while inferential results depend on a model and analysis method. The record gives enough information to describe means, standard deviations, the posted contrast, and its interval and p-value, but it does not report the full statistical plan, handling of missing data, or analysis populations. Those limits make transparent interpretation more appropriate than assuming methods that are not documented.

11. Confidence Intervals and Precision

The primary mean-difference estimate is -30.2, and its confidence interval extends from -39.34 to -21.06. The entire interval is below zero, indicating that the reported estimate and its interval are in the direction of a lower pain score on the Restylane-L side. The interval conveys uncertainty about the average contrast, not the range of pain scores experienced by individual participants.

The side-specific standard deviations are 31.5 for Restylane and 17.7 for Restylane-L. These describe variability among the recorded scores. They do not by themselves supply the standard error of a paired difference, because the degree of association between the two scores from each participant is not given. The registry record does not state the confidence level or the method behind the interval, and it does not report a confidence interval for each side’s mean.

Precision should therefore be judged from the posted interval as reported, while recognizing that key details of its construction are absent. The interval’s placement below zero is distinct from the size of the mean difference, and neither quantity captures every individual response. The estimate is based on 60 participants, each receiving both products, but the record does not explain how missing or incomplete measurements, if any, were handled.

In general, greater precision means less uncertainty around an estimate, whereas statistical significance alone does not say whether an estimate is precise enough for a particular use. No threshold for a meaningful difference is reported, so the clinical importance of a particular score contrast cannot be determined from statistical precision alone.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are stated as participants per arm, not as total event counts. They are illustrations based on the observed effect and its stated fractions; they do not report the original enrollment calculation for this study. The registry record does not report the trial’s own sample-size justification or original planning assumptions.

The stated assumptions for the illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. For planning for 100% of the observed effect, the illustration gives 12 participants per arm for 80% power and 16 participants per arm for 90% power. For planning for 75% of the observed effect, the corresponding figures are 20 and 27 participants per arm. For planning for 50% of the observed effect, they are 45 and 61 participants per arm.

In plain language, the 80% power column describes the participant count per arm under which the planning model would have an 80% chance of detecting the specified effect at the stated significance level, if its assumptions hold. The 90% column describes the corresponding planning target for a 90% chance. These are conditional planning calculations, not guarantees about a future study’s result. Smaller effects need more participants to detect under otherwise unchanged assumptions, which is why the illustrations increase as the target effect becomes a smaller fraction of the observed effect.

These figures are not observed power. They should not be read as evidence about the trial’s actual probability of detecting an effect, nor as a retrospective judgment of whether the completed study was adequately sized. They use a normal approximation and equal allocation between arms, while the trial enrolled participants in a split-face design. Their role is to illustrate how sample-size requirements vary with a chosen effect size under the stated assumptions.

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 = -30.200; pooled standard deviation σ = 25.549.
2. n = 2 × (1.96 + 0.842)² × 25.549² / -30.200² = 11.2, rounded up to 12 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 <- -30.2                      # observed difference in means
sigma <- 25.549363984256                     # 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(797459)
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 = 12 (80% power), 16 (90% power)
 75% of observed effect: n per arm = 20 (80% power), 27 (90% power)
 50% of observed effect: n per arm = 45 (80% power), 61 (90% power)
power.t.test: 12.3 
Simulated power at n = 12 per arm: 0.786 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary pain outcome and one secondary outcome for wrinkle improvement at Day 14. It does not report a multiplicity strategy, such as a procedure for controlling error across outcomes or a formal hierarchy specifying how the endpoints were to be tested. The posted p-values are unadjusted. This matters because statistical testing across multiple endpoints can make chance findings more likely if each test is considered in isolation.

The absence of a reported multiplicity plan does not invalidate the numerical summaries, but it limits the strength of confirmatory claims based on secondary testing. The primary outcome is the main endpoint named in the record, yet the full prespecified statistical analysis plan is not reported. It is also not reported whether interim analyses took place, or how they might have affected interpretation. No assumptions about those procedures should be made.

Missing-data handling is not reported in the registry record. Although the posted primary outcome includes 60 observations for each side, the record does not explain whether all randomized or enrolled participants contributed complete paired scores, how incomplete observations were handled, or whether any imputation was used. A count of 60 for each side does not by itself establish that every participant had a complete matched pair available for analysis.

The analysis populations are also not reported. The record does not specify whether results use all enrolled participants, only participants who received treatment, participants with evaluable outcomes, or another defined group. It does not provide exclusions or deviations from the intended analysis population. These details can affect how results are interpreted and whether the estimates align with the randomized study population.

Finally, the record contains no formal analysis entries. It gives outcome summaries and comparisons but does not document the analysis protocol in enough detail to assess all assumptions, adjustments, or sensitivity analyses. This is a reporting limitation, not evidence that such methods were or were not used.

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 1% reporting threshold.

Most frequent non-serious adverse event terms

The adverse-event figures record no participants affected by serious adverse events on either side: 0 of 60 for the Restylane-L side and 0 of 60 for the Restylane side. No serious-event terms are listed. The registry record does not report death counts, so that information should not be inferred from the absence of a number.

For other, non-serious adverse events, 46 of 60 participants are recorded on each side. These are side-specific counts in a split-face study, not counts from two independent participant groups. The figures alone do not identify event types, severity beyond the serious/non-serious distinction, timing, duration, or whether the same participants experienced events on both sides.

Zero recorded serious events in this study does not establish that serious events cannot occur. The study enrolled 60 participants and the posted counts describe only the registry record’s observed data. The record does not report further detail on event collection or attribution, so the counts should be read narrowly and not as a complete assessment of every safety question.

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

The posted primary result describes a lower average pain score on the Restylane-L side than on the Restylane side among the 60 participants who received both products. The mean difference is -30.2, and the confidence interval from -39.34 to -21.06 lies below zero. The unadjusted p-value is <0.001. Together, these statistics describe the direction and estimated size of the observed average contrast and its reported statistical uncertainty.

They do not show that every participant had less pain on the Restylane-L side. Group averages can conceal variation between individuals, and the registry does not report the distribution of within-person differences. They also do not establish how the result would generalize beyond the participants studied, since the record does not provide enough population detail to assess representativeness.

The endpoint is specifically pain measured after injection on the treatment day. It does not establish a difference in pain at other times, long-term tolerability, or outcomes not measured in the record. The secondary Day 14 improvement result is a separate outcome, with its own uncertainty and reporting limitations. The posted data do not justify treating that outcome as interchangeable with the pain score.

Statistical evidence is not the same as a judgment of practical or clinical importance. The record does not state a threshold for a meaningful difference on the visual analogue scale. Consequently, the numerical contrast and its interval can be described, but a threshold-based judgment cannot be made from this information alone.

Nor does the primary result establish the full safety profile. The serious adverse-event counts are limited observations, and the event descriptions and deaths are not fully reported. The most defensible interpretation remains specific: the registered summaries show lower average treatment-day pain scores on the Restylane-L side, with uncertainty represented by the posted interval, in this split-face study.

17. Why This Trial Matters Statistically

This study illustrates how a split-face design changes the structure of a clinical comparison. Each participant received both products, so the measurements are paired rather than arising from unrelated treatment groups. That feature can make within-person contrasts informative, but it also means that a complete account of the analysis should explain how the pairing was handled. The registry record gives side-specific summaries and a contrast without documenting that methodological detail.

The results also demonstrate why effect estimates, uncertainty intervals, and p-values answer different questions. The mean difference gives the estimated direction and magnitude of the average contrast. The confidence interval communicates uncertainty around that estimate, while the p-value evaluates compatibility with a null model under a test. None alone gives a complete interpretation, and a statistically small p-value does not determine the practical importance of an effect.

Finally, the record distinguishes a primary outcome from a secondary outcome but does not report a multiplicity plan or full analysis strategy. That gap highlights the value of transparent reporting of endpoint hierarchy, missing-data handling, analysis populations, and methods for paired observations. Without those details, readers can interpret the posted numerical summaries while remaining appropriately cautious about how they were produced and how broadly they apply.

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 most specific limitation is that the study’s split-face structure is not matched by a fully documented statistical analysis. The record reports means and standard deviations for each side and a mean difference, but does not state whether the primary comparison used a paired method or how it handled within-person dependence. The marginal summaries do not reveal the variability of participant-level differences.

The registry record also does not report the confidence level for the primary interval, the original sample-size rationale, or the complete statistical plan. It does not state whether there were interim analyses, how missing data were handled, or which analysis populations were used. Those omissions constrain assessment of precision, potential bias, and the relationship between the posted results and the planned analysis.

Participant characteristics are not described in the posted outcome information, limiting assessment of how representative the enrolled group may be. Details of randomization beyond the randomized designation and the participant blinding to treatment side are also not reported. The record does not give additional information about the pain-score collection process or the definition and assessment of wrinkle improvement.

The primary outcome reflects pain immediately after injection on the treatment day, so it addresses a limited time point. The secondary outcome is recorded at Day 14, but only one secondary endpoint is posted. The adverse-event information lacks event terms and fuller details, and death counts are not reported. These features do not negate the reported statistics, but they limit the range of conclusions that can be drawn from them.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety & Tolerability Study That Compares Restylane to Restylane With Lidocaine While Correcting Wrinkles in the Nasolabial Folds — NCT00797459.
• Registry record last updated 2013-09-06; status last verified 2013-08.
• Results first posted 2011-02-21.
• 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

NCT00797459 is a completed randomized, double-blind split-face study comparing Restylane with Restylane-L during correction of nasolabial folds. A total of 60 participants received both products once, with each product applied to a different side of the face.

The primary outcome was pain on a visual analogue scale after injection on the treatment day. The posted mean score was 44.9 for Restylane and 14.7 for Restylane-L; the reported mean difference for Restylane-L relative to Restylane was -30.2, with a confidence interval from -39.34 to -21.06 and an unadjusted p-value of <0.001. One secondary outcome, wrinkle improvement at Day 14, is also recorded.

The registry lists no participants affected by serious adverse events on either side. It does not report the full statistical plan, analysis populations, missing-data handling, multiplicity strategy, or death counts.