RHA® Redensity With New Anesthetic Agent - Perioral Rhytids: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for RHA® Redensity With New Anesthetic Agent - Perioral Rhytids (NCT04069585), a randomized na study. The primary outcome is Non-inferiority of RHA® Redensity With New Anesthetic Agent Versus RHA® Redensity With Lidocaine in Terms of Reducing Pain During Device Injection Into the Upper Perioral Rhytids..

2. Clinical Question

3. Trial Design

This was a randomized, controlled, double-blinded, multicenter, prospective study. Its description specifies a within-subject, split-face design: each participant received RHA® Redensity with the new anesthetic agent on one side of the mouth and RHA® Redensity with lidocaine on the other. Randomization determined the side and injection sequence for the new-anesthetic formulation. The participant and the treating investigator injecting the devices were described as blinded.

The registry lists masking as triple, but does not identify all roles covered by that label. It also lists the model as parallel while the study description and arm descriptions specify split-face treatment. These labels are not reconciled in the registry record. For interpreting the clinical comparison, the within-person allocation is important: the two formulation ratings come from sides treated in the same participant, rather than from separate participant groups.

The recorded enrollment was 30, and the primary outcome population description says participants were enrolled and treated. Each arm’s posted summary statistics also list 30 participants. The registry record gives the start date as 2019-10-30, primary completion as 2020-02-24, and status as completed. Phase is listed as NA.

At screening, the treating investigator assessed perioral rhytid severity with the Perioral Rhytid Severity Rating Scale (PR-SRS). The registry describes pain ratings immediately after injection and further pain assessments at 15, 30, 45 and 60 minutes after injection of the upper quadrant. A safety follow-up call was planned at 72 hours, a 30-day Common Treatment Response diary was used, and a second visit for efficacy and safety assessments was scheduled 30 days after injection. These are aspects of the study’s recorded assessment schedule; they do not establish that every assessment was completed for every participant.

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: There were 30 participants enrolled and treated, the participants received bilateral, split-face treatment into the upper perioral rhytids.

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 Non-inferiority of RHA® Redensity With New Anesthetic Agent Versus RHA® Redensity With Lidocaine in Terms of Reducing Pain During Device Injection Into the Upper Perioral Rhytids., measured over Visit 1 - During Injection.

The primary endpoint was pain during injection of the upper perioral rhytids, assessed at Visit 1. Immediately after each upper perioral quadrant was injected, participants rated the pain they had experienced using a 100 mm Visual Analog Scale. The registry defines 0 as no pain and 100 as intolerable pain. The posted outcome is expressed as a mean with standard deviation, in millimeters.

The endpoint addresses a direct experience of the procedure: the participant’s rating of pain during injection, rather than an investigator’s assessment of appearance or a later report of discomfort. A continuous scale preserves variation across ratings instead of reducing responses to categories. As a general statistical point, a mean describes the average rating, while the standard deviation describes how dispersed individual ratings are around that average. Neither quantity alone describes the experience of every participant.

The study’s stated primary objective was non-inferiority of the new-anesthetic formulation relative to the lidocaine formulation for reducing pain during injection. A non-inferiority question asks whether the outcome for the candidate formulation is not worse than the comparator by more than a prespecified acceptable margin. The margin is essential to interpreting that question, but it is not reported in the registry record. The primary outcome is specifically the rating during injection; later pain assessments are listed as secondary outcomes and should not be substituted for this endpoint.

7. Results Posted in the Registry

• RHA® Redensity With New Anesthetic Agent: mean 25.00 versus 22.40 on control; difference 2.60 (95% CI -9.77 to 14.97), standardized effect d = 0.11; z-test p = 0.680.

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome is continuous: pain was measured on a scale in millimeters, and the registry reports a mean and standard deviation for each formulation. A mean summarizes the central level of ratings, while a standard deviation summarizes their spread. These statistics are descriptive. They do not show the full distribution of ratings, and they do not tell how often participants chose any particular part of the scale.

What does the split-face design change?

In a split-face study, each participant receives both formulations, one on each side. The comparison is therefore naturally paired: the difference between a participant’s two ratings can be considered before summarizing differences across participants. Pairing can control for participant characteristics shared across the two sides, because those characteristics do not vary between the participant’s own treatments. This is a general feature of within-subject designs, not a statement about the specific analysis used in this trial.

To analyze paired data, the variability of the within-participant differences is relevant. It depends not only on the separate arm standard deviations but also on how the two ratings are correlated within a participant. The registry reports arm means and standard deviations, but the within-participant covariance or standard deviation of paired differences is not reported in the registry record. Consequently, the posted arm summaries alone do not reveal the full information needed to reproduce a paired analysis.

What does a mean difference describe?

The recalculated mean difference is 2.6 mm, defined as the new-anesthetic mean minus the lidocaine mean. A positive value means the posted mean rating was higher in the new-anesthetic arm; a negative value would mean it was lower. This direction describes the arithmetic contrast, not a judgment about clinical importance. Whether a difference of any particular size is acceptable depends on a clinical criterion, including the non-inferiority margin for the trial’s stated objective. That margin is not reported in the registry record.

The recalculated 95% confidence interval runs from -9.773 to 14.97. In general, a confidence interval represents a range of values compatible with the estimate under the statistical method and its assumptions. It communicates uncertainty about the mean difference more directly than a single p-value. This interval is from the unadjusted recalculation, not the sponsor’s reported test, and should not be treated as the confidence interval for the sponsor analysis.

What do the two p-values refer to?

The registry gives an unadjusted recalculated p-value of 0.68 alongside the summary-statistic comparison. A p-value in a difference test measures how incompatible the observed data are with a specified null hypothesis, under the model used. It is not the probability that the null hypothesis is true, and it does not measure the probability that the result will repeat. The registry does not provide enough detail to treat this recalculation as a reproduction of the prespecified sponsor analysis.

The sponsor’s reported method is a one-sided t-test labelled NON INFERIORITY, with p < 0.001. A one-sided non-inferiority test evaluates a directional question against a margin, rather than simply asking whether the two means differ in either direction. The result depends on the margin and on the analysis specification. Neither the margin nor the detailed statistical plan is reported in the registry record. Since the sponsor analysis and the recalculation do not agree, the sponsor’s own analysis takes precedence for interpreting the trial’s reported non-inferiority result; the available registry entries do not allow the discrepancy to be resolved.

Why can over-dispersion matter?

As a general statistical concept, over-dispersion means that observations vary more than a model expects. When a model assumes less variability than the data contain, standard errors can be too small and intervals can be too narrow. The posted standard deviations, 23.21 and 25.63, describe substantial variation in ratings relative to the scale’s endpoints, but those summaries alone do not establish that a particular model was over-dispersed or misspecified. The registry record does not provide diagnostic information about model fit.

What is and is not reported about the analysis?

The registry lists one reported analysis, described as a one-sided t-test for non-inferiority. The record does not state whether the test used paired differences, how missing outcome ratings were handled, which analysis population was used for the sponsor’s test, or whether the test adjusted for any additional factors. The original sample-size assumptions, including the planned treatment effect and non-inferiority margin, are not reported in the registry record. These omissions limit independent assessment of how the sponsor’s result was produced.

The posted recalculation is an unadjusted comparison based on summary statistics. It is useful for reading the means and their broad uncertainty, but it is not a substitute for the trial’s own analysis. In particular, it does not establish that the sponsor’s method, its assumptions, or its treatment of within-person pairing have been reproduced.

10. Confidence Intervals and Precision

The recalculated mean difference is 2.6 mm, with a 95% confidence interval from -9.773 to 14.97. The interval includes zero and extends to values in both directions. It therefore communicates uncertainty about whether the average pain rating was higher or lower with the new-anesthetic formulation in this unadjusted comparison. The interval’s width also indicates that the summary comparison does not pinpoint a narrow range of plausible mean differences.

In general, a confidence interval is a range produced by a statistical procedure that reflects sampling uncertainty under its assumptions. It is not a range containing a specified proportion of individual participants’ ratings, and it does not guarantee that the true effect lies within the particular interval. Here, the stated interval belongs to the recalculated summary comparison. The sponsor’s non-inferiority interval is not reported in the registry record.

The arm standard deviations are 23.21 mm for lidocaine and 25.63 mm for the new anesthetic agent. They describe variation among the ratings within each arm, but do not reveal how closely each participant’s two side-specific ratings correspond. Because this is a split-face comparison, the unreported within-person association is relevant to precision for a paired treatment contrast.

For a non-inferiority question, precision must be interpreted relative to the acceptable margin. The registry record does not report that margin, so the recalculated interval cannot be used to determine whether the candidate formulation falls within the trial’s non-inferiority criterion. The sponsor reports a one-sided non-inferiority test with p < 0.001, but the estimate and interval for that analysis are not reported in the registry record. The sponsor result and the unadjusted recalculation therefore answer different statistical descriptions and should not be conflated.

11. Planning a Similar Trial: Sample Size

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

The planning figures are participants per arm for 80% power and participants per arm for 90% power. They are not total event counts. For planning for 100% of the observed effect, the figures are 1,389 participants per arm for 80% power and 1,859 participants per arm for 90% power. For planning for 75% of the observed effect, they are 2,468 and 3,304 participants per arm, respectively. For planning for 50% of the observed effect, they are 5,553 and 7,434 participants per arm, respectively.

In plain terms, the 80% power column describes the planning size associated with an 80% chance of detecting the specified effect under the stated assumptions if that effect is present. The 90% column uses a higher target chance of detection and consequently gives larger planning figures. These are planning illustrations based on the observed effect, not observed power.

The calculation assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The original trial’s own sample-size assumptions are not reported in the registry record, so these planning scenarios should not be read as the enrollment target used to design this study. Smaller effects require more participants to detect under otherwise unchanged assumptions, which is why the planning figures rise as the target fraction of the observed effect falls.

12. 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 = 2.600; pooled standard deviation σ = 24.450.
2. n = 2 × (1.96 + 0.842)² × 24.450² / 2.600² = 1,388.2, rounded up to 1,389 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 <- 2.6                      # observed difference in means
sigma <- 24.4499591001703                     # 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(4069585)
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 = 1,389 (80% power), 1,859 (90% power)
 75% of observed effect: n per arm = 2,468 (80% power), 3,304 (90% power)
 50% of observed effect: n per arm = 5,553 (80% power), 7,434 (90% power)
power.t.test: 1389.1 
Simulated power at n = 1,389 per arm: 0.799 (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.

13. Analyses Reported by the Sponsor

The sponsor’s posted result is a one-sided t-test for non-inferiority with p < 0.001. The registry does not report the non-inferiority margin, the sponsor’s estimated treatment difference, or a confidence interval for that analysis. Without those details, the test cannot be independently reconstructed from the registry record.

The separate recalculation from the posted arm summaries gives a mean difference of 2.6 mm, a 95% confidence interval from -9.773 to 14.97, and an unadjusted p-value of 0.68. This is a simple unadjusted comparison and is not the sponsor’s non-inferiority analysis. A difference test and a non-inferiority test have different hypotheses and interpretations, and the split-face design also makes the handling of paired ratings relevant.

The registry flags a discrepancy between the sponsor analysis and the recalculation. In that situation, the sponsor’s own analysis takes precedence for the trial’s reported non-inferiority result. The recalculation remains useful as a transparent reading of the posted means and uncertainty, but it should not replace the sponsor’s analysis or be presented as a replication of it. The available record does not explain the discrepancy.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary pain endpoint and 8 secondary outcomes. The secondary outcomes include pain at 15, 30, 45 and 60 minutes, change in PR-SRS score, responder status based on PR-SRS improvement, subject perception on the FACE-Q Perioral Rhytids domain, investigator and subject global aesthetic improvement, satisfaction, and post-injection treatment responses. Multiple outcomes create the possibility of multiple statistical tests. As a general concept, testing many outcomes can increase the chance of at least one apparently notable result by chance if no adjustment or hierarchy is used.

The registry record does not report whether multiplicity was addressed, whether secondary outcomes were exploratory, or whether an order of testing was specified. The original statistical analysis plan and detailed protocol are not reported in the registry record. The sponsor’s posted analysis is described as a one-sided t-test for non-inferiority, but the registry does not provide the margin or a fuller account of the testing procedure.

Missing-data handling is not reported in the registry record. The record describes 30 participants enrolled and treated and gives 30 participants in each arm’s summary, but does not explain whether all participants contributed a primary rating, how any absent rating was handled, or whether exclusions occurred in the sponsor analysis. It also does not describe an imputation method or a sensitivity analysis for missing outcomes.

The analysis population used for the sponsor’s non-inferiority test is not reported in the registry record. In non-inferiority settings, the choice and definition of analysis populations can be important, but the registry does not say whether an intention-to-treat, per-protocol, or other population was used. The record also does not specify how the split-face pairing was incorporated into the sponsor’s analysis. These gaps constrain evaluation of multiplicity, missingness, and analysis-population robustness; they do not establish that any particular procedure was or was not used.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: osteomyelitis (toe on left foot) (3.3%).

The registry lists serious adverse events in 1 participant at risk in the new-anesthetic-agent group and 1 participant at risk in the lidocaine group. It lists other adverse events affecting 6 participants in the new-anesthetic-agent group and 5 in the lidocaine group. Deaths are recorded as 0 in both groups. Each group lists 30 participants at risk. The serious-event term reported among the top terms is “Osteomyelitis (toe on left foot)” at 3.3%.

These registry counts describe reported safety entries; they do not establish that a treatment caused an event. The record does not provide enough detail to determine the timing, severity beyond the serious-event classification, relatedness assessments, or whether an event occurred in a participant exposed to both formulations. The listed serious-event term is not assigned to a specific formulation in the reported information. The counts also do not describe all possible dimensions of safety or the uncertainty around the event frequency. They should be read as the posted adverse-event figures, not as a complete causal comparison of the formulations.

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

The posted means describe average injection-pain ratings of 22.4 mm with lidocaine and 25.0 mm with the new anesthetic agent. The unadjusted recalculation gives a mean difference of 2.6 mm for new anesthetic agent minus lidocaine, with a 95% confidence interval from -9.773 to 14.97. The interval includes values in both directions, so these summary statistics do not provide a precise estimate of the direction or size of the mean difference.

The sponsor reported a one-sided non-inferiority t-test with p < 0.001. The registry record does not report the non-inferiority margin or the sponsor’s estimated difference and confidence interval. As a result, the sponsor’s reported test cannot be independently evaluated against the margin from the registry information. Because the registry flags a discrepancy, the sponsor’s own analysis takes precedence for the trial’s stated non-inferiority result, while the unadjusted recalculation should be understood as a separate summary-statistic comparison.

These results do not establish that the formulations produce identical pain ratings. A non-inferiority finding, when interpreted with its margin and analysis, addresses whether a difference exceeds an acceptable boundary; it does not demonstrate exact equality. Conversely, the recalculated interval’s inclusion of zero does not establish non-inferiority. The two conclusions are not interchangeable.

The finding also concerns pain during injection in the studied setting and measured by the specified VAS. It does not answer whether the formulations differ in later pain, aesthetic improvement, satisfaction, or safety. Those outcomes are listed in the registry, but their results are not reported in the registry record for this interpretation. The sample-size planning illustrations are not observed power and do not establish the precision or reliability of this completed trial’s result.

17. Why This Trial Matters Statistically

This study illustrates why the design and statistical question must be read together. A split-face design compares two formulations within the same participant, while the stated primary objective is non-inferiority. The first feature makes the within-person pairing important for estimating uncertainty; the second requires a prespecified acceptable margin. The registry record does not report the sponsor’s margin or explain how paired observations entered its test.

The distinction between the sponsor’s non-inferiority analysis and a recalculated difference comparison is central. The sponsor reports a one-sided t-test with p < 0.001, while the unadjusted summary-statistic recalculation gives a mean difference of 2.6 mm, a 95% confidence interval from -9.773 to 14.97, and an unadjusted p-value of 0.68. Those results should not be collapsed into a single claim: they represent different analyses, and the registry flags a discrepancy. The sponsor analysis takes precedence for the trial’s reported non-inferiority result, but missing details prevent independent reproduction.

The record also shows how a small observed difference can coexist with substantial uncertainty. The arm standard deviations are 23.21 and 25.63 mm, and the recalculated interval spans both negative and positive differences. General statistical interpretation therefore calls for attention to the interval and analysis assumptions, rather than relying on the mean difference or a p-value alone. The listed planning illustrations reinforce that the number of participants needed depends on the effect chosen for detection and on the assumed design parameters, not just on the observed trial size.

Finally, registry reporting is part of statistical interpretation. Details about the non-inferiority margin, missing data, analysis population, multiplicity, and paired analysis would help readers assess what the reported test means and how it relates to the posted descriptive results. Their absence limits independent assessment without, by itself, proving that the underlying trial did not specify them.

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 gives limited information for judging the population to which the findings apply. It reports 30 participants enrolled and treated but does not report participant ages, baseline pain characteristics, demographic composition, or detailed eligibility criteria in the registry record for this interpretation. The study concerns injection into upper perioral rhytids, so the recorded pain comparison is specific to that procedure and assessment context.

The registry describes randomized treatment side and sequence, but does not report details of the randomization method or allocation concealment. Although masking is listed as triple and the description says participants and the treating investigator injecting the devices were blinded, the identities of all roles covered by triple masking are not reported in the registry record. The record’s parallel model label is also not reconciled with its split-face, within-subject description.

Important analysis details are missing. The non-inferiority margin, sponsor’s effect estimate and confidence interval, paired-analysis specification, missing-data method, analysis population, and any multiplicity procedure are not reported in the registry record. The reported sponsor p-value and the unadjusted recalculation differ, and the record does not explain the discrepancy. These limitations prevent independent reconstruction of the sponsor’s analysis.

The registry lists secondary assessments but their results are not reported in the information. The posted adverse-event figures are limited summaries and do not establish causation or provide a complete account of event timing and relatedness. These constraints call for a narrow reading of the evidence: the posted primary pain summaries and sponsor test can be described, but the record does not support broader conclusions about other outcomes or about all aspects of treatment safety.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: RHA® Redensity With New Anesthetic Agent - Perioral Rhytids — NCT04069585.
• Registry record last updated 2022-01-24; status last verified 2021-05.
• Results first posted 2021-06-16.
• 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

NCT04069585 is a completed randomized, controlled, double-blinded, multicenter, prospective study comparing RHA® Redensity with a new anesthetic agent against RHA® Redensity with lidocaine for pain during injection into upper perioral rhytids. The study description specifies a split-face, within-subject design, with randomized treatment side and sequence. The record lists enrollment of 30 and records the study start as 2019-10-30 and primary completion as 2020-02-24.

The primary outcome was participant-rated injection pain on a 100 mm VAS. Posted means were 22.4 mm for lidocaine and 25.0 mm for the new anesthetic agent. The sponsor reported a one-sided non-inferiority test with p < 0.001; the margin and further analysis details are not reported in the registry record. An unadjusted recalculation gives a mean difference of 2.6 mm, with a 95% confidence interval from -9.773 to 14.97 and p = 0.68. Because the registry flags a discrepancy, the sponsor’s own analysis takes precedence for the trial’s reported non-inferiority result.