Evaluation of Pain With Belotero® Balance With Integral Lidocaine for Correction of the Nasolabial Folds: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Pain With Belotero® Balance With Integral Lidocaine for Correction of the Nasolabial Folds (NCT03319719), a randomized na study. The primary outcome is Mean Pain Using Visual Analog Scale (VAS).

2. Clinical Question

3. Trial Design

The registry describes a randomized, triple-masked, parallel study with an enrollment of 52. It also describes a split-face design: each product was injected into one of the participant's two nasolabial folds, and the treatment side was randomized. These design descriptions are both recorded; further detail about how the parallel-model label relates to the split-face description is not reported in the registry record.

The test product was Belotero Balance with integral lidocaine, and the control product was Belotero Balance without lidocaine. The registry lists both as device interventions. The trial's stated purpose was to assess injection-related pain and to identify and describe adverse events, serious adverse events, and common treatment site responses.

The study was completed. Its recorded start date was 2017-09-18, and its primary completion date was 2017-12-06. Phase is listed as not applicable. The sponsor was Merz North America, Inc.

The primary endpoint was measured on Day 1 immediately after injection. The registry also lists secondary outcomes concerning fold-scale response at Week 6, adverse events, and treatment site responses recorded in participant diaries. The registry record does not report the original sample-size justification or the design assumptions used to plan the trial.

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: A total of 65 participants were screened, out of which 52 participants were randomized and treated. Of these, 51 participants completed the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The full analysis set (FAS) included all randomized participants and were analyzed as randomized.

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: The safety evaluation set (SES) included all participants who were enrolled into the study, randomized, and received an injection.

6. Primary Endpoint

The registry lists the primary outcome as Mean Pain Using Visual Analog Scale (VAS), measured over Day 1.

The primary endpoint was mean pain on a visual analog scale (VAS), assessed separately for each nasolabial fold immediately after injection on Day 1. The VAS ranged from 0, meaning no pain, to 10, meaning very severe pain. Its description specifies 21 numbered circles at 0.5 cm increments across a 10 cm scale, anchored by word descriptors.

Pain is a continuous measure in this analysis, and the endpoint summarizes participants' scores as a mean for each product. Comparing the means addresses the trial's stated question about injection-related pain. The registry's primary endpoint description emphasizes the immediate assessment, so it concerns pain at completion of injection rather than later pain or an overall experience across the study.

In general, a standardized scale makes the measurement approach explicit and supports a direct comparison of scores between treatment conditions. A mean gives a concise group-level summary, while the standard deviation describes how dispersed individual scores were around that mean. Neither summary alone shows every participant's experience. The registry record does not report additional details about the VAS's validation or how scores were handled if an assessment was missing.

7. Results Posted in the Registry

• Test Product: BBL: mean 3.07 versus 5.94 on control; difference -2.87 (95% CI -3.70 to -2.04), standardized effect d = -1.33; 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.

Percentage of Responders With Greater Than or Equal to (>=) 1-point Improvement as Evaluated Using Merz NLF Scale at Week 6

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Test Product: BBL: 51.0% (26/51) versus 52.9% (27/51) on control; risk difference -2.0 percentage points (95% CI -21.3 to 17.4), risk ratio 0.96 (0.66–1.40); unadjusted two-proportion z-test p = 0.843.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Test Product: BBL and the control. The interval gives the range of effects that remain compatible with the data.

Number of Participants With Incidence of Any Common Treatment Site Response (CTR) Evaluated Using Participant Diaries

• 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:
  • Test Product: BBL: 78.8% (41/52) versus 86.5% (45/52) on control; risk difference -7.7 percentage points (95% CI -22.2 to 6.8), risk ratio 0.91 (0.76–1.09); unadjusted two-proportion z-test p = 0.300.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Test Product: BBL and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary results address more than one kind of outcome: fold-scale response at Week 6, treatment-emergent adverse events and serious adverse events, and common treatment site responses described by incidence, severity, and duration. Results are available for the Week 6 responder outcome and the incidence of any common treatment site response. Results for the other listed secondary outcomes are not reported in the registry record.

Across the secondary outcomes with posted comparative data, the estimates do not show a clear separation between products: the confidence intervals for the reported risk differences include zero, and the unadjusted p-values are not small. This is a broad description of their statistical pattern, not a conclusion that the products are equivalent. The outcomes concern different measures and timeframes from the immediate Day 1 pain endpoint, so they do not directly confirm or contradict the primary result.

In general, testing several outcomes raises a multiplicity concern: the chance of at least one apparently notable result can increase when many comparisons are made. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting secondary outcomes. The secondary comparisons are unadjusted, and their results should therefore carry less weight than the primary analysis when drawing an overall statistical interpretation. The record also does not report whether every listed secondary analysis was planned before examining the data.

Secondary findings are best considered descriptive and outcome-specific. They can add context about the measured response and safety outcomes, but they do not change what the primary endpoint measured. Missing results for some listed outcomes limit how completely the secondary outcome set can be assessed.

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

• Percentage of Responders With Greater Than or Equal to (>=) 1-point Improvement as Evaluated Using Merz NLF Scale at Week 6
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
• Number of Participants With Incidence of Any Common Treatment Site Response (CTR) Evaluated Using Participant Diaries
• Number of Participants With Incidence of Any CTR by Severity Evaluated Using Participant Diaries
• Number of Participants With Incidence of Any CTR by Duration Evaluated Using Participant Diaries

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: each fold has a numerical VAS score, and the registry reports a mean and standard deviation for each product. In general, a mean estimates the central level of a set of measurements. A standard deviation describes how much observations vary around that mean; it is not the uncertainty of the mean itself.

What does the mean difference represent?

The mean difference compares the test-product mean with the control-product mean. The posted re-calculation is -2.87, with the test product first in the comparison. A negative value therefore indicates that the test-product mean was lower in the posted data. The estimate is expressed in VAS score units. It is not a percentage change or a count of participants.

What does the t-test assess?

The registry reports a two-sided t-test for the mean difference. In general, a t-test evaluates whether a difference in group means is compatible with a null value of zero, while accounting for sampling variability under the test's assumptions. A two-sided test considers departures in either direction rather than only a lower or higher score. The registry does not report further details about the test implementation, including whether it accounted for the split-face pairing.

Why does the split-face design matter?

In a split-face design, each participant receives both conditions on different sides. In general, scores from the same participant may be more alike than scores from different participants. A paired analysis can account for that relationship by comparing the two sides within each participant. The posted summary-statistic re-calculation is described as a simple, unadjusted re-calculation; it does not reconstruct an analysis of participant-level paired differences. The participant-level paired data and details needed to independently reproduce such an analysis are not reported in the registry record.

The registry's sample counts are 52 for each primary treatment condition. Those are the posted numbers of observations for the two sides, not evidence that there were 104 different participants. The overall enrollment is 52, and the design description places both treatment conditions within a participant.

How should the p-value be read?

In general, a p-value describes how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the test assumptions held. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The re-calculated p-value is p < 0.001. The sponsor reports a p-value below < 0.001; no additional precision is needed to understand that both reported tests indicate strong statistical evidence against a zero mean difference under their respective analysis assumptions.

A small p-value does not remove uncertainty about the estimated difference. The confidence interval is useful for seeing a range of values compatible with the analysis, subject to its assumptions. Its interpretation is addressed separately in the precision discussion.

What does over-dispersion mean in general?

For a continuous outcome, the standard deviation conveys the observed spread rather than a separate model for over-dispersion. In general, over-dispersion is a concern when observed variability is greater than a statistical model expects. If a model understates variability, its uncertainty estimates can be too narrow and its tests can appear more decisive than warranted. The registry record does not report an over-dispersion analysis, and the posted primary endpoint is summarized with means and standard deviations.

The secondary outcomes include binary measures, such as whether a participant met a response definition or had a treatment site response. In general, binary outcomes are summarized by counts or proportions, and a risk difference compares proportions between conditions. Such analyses have their own uncertainty and assumptions; their unadjusted results should not be treated as if they were the prespecified primary test.

All explanations of statistical concepts in this discussion are general. The registry record does not report a full statistical analysis plan, the original planning assumptions, or enough participant-level data to reproduce all analyses independently.

11. Confidence Intervals and Precision

The sponsor's 95% confidence interval for the primary mean difference runs from -3.42 to -2.33. The simple unadjusted re-calculation gives a 95% confidence interval from -3.701 to -2.039. Both intervals are entirely below zero, and each indicates that the estimated mean pain score was lower for the test product in the posted comparison.

In general, a confidence interval describes the precision of an estimate under the analysis assumptions. It gives a range of values compatible with the data and method; it is not a guarantee that the true value lies in that particular interval. An interval's width reflects uncertainty, and a narrower interval generally indicates greater precision than a wider one under comparable methods.

The sponsor and re-calculated intervals are not identical. The registry record reports the sponsor's two-sided t-test, while the re-calculation uses posted summary statistics and is explicitly unadjusted. Because the study is described as split-face, the within-participant relationship may matter to uncertainty estimation. The participant-level paired data and full implementation details are not reported in the registry record, so the re-calculation should be read as an approximation from the posted summaries, not as an independent reconstruction of every analysis detail.

The intervals concern the mean difference in immediate VAS pain scores. They do not describe the range of individual scores, later pain, secondary outcomes, or safety events. The registry record does not report a prespecified threshold for an important difference on the scale, so statistical precision alone cannot establish the practical importance of the estimated difference.

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 participants per arm, not total events. The sample-size illustration uses a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It considers detecting a stated fraction of the observed effect. The original trial's own sample-size assumptions and justification are not reported in the registry record.

The 80% power column describes the number of participants per arm that the illustration estimates would be needed to have an 80% chance of detecting the specified effect if that effect and the planning assumptions held. The 90% power column gives the corresponding planning number for a 90% chance. These are design calculations, not descriptions of what happened in the completed study.

Rows that plan for 100% of the observed effect use the full observed estimate as the target; rows that plan for 75% or 50% use smaller target effects. Smaller effects are harder to distinguish from random variation, so the illustration requires more participants as the target effect becomes smaller. The figures are scenario-based and depend on the observed effect used as their starting point.

This is not observed power. It is a planning illustration based on the posted effect and stated assumptions, not a measure of the probability that the completed trial successfully detected an effect. The trial enrolled 52 participants, but that enrollment should not be compared with an illustrative requirement without recognizing that the calculation is not the original design justification and that the split-face design may affect the appropriate analysis.

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 = -2.870; pooled standard deviation σ = 2.161.
2. n = 2 × (1.96 + 0.842)² × 2.161² / -2.870² = 8.9, rounded up to 9 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 <- -2.87                      # observed difference in means
sigma <- 2.1613074746551                     # 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(3319719)
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 = 9 (80% power), 12 (90% power)
 75% of observed effect: n per arm = 16 (80% power), 22 (90% power)
 50% of observed effect: n per arm = 36 (80% power), 48 (90% power)
power.t.test: 10 
Simulated power at n = 9 per arm: 0.756 (20000 replicates)

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

14. Analyses Reported by the Sponsor

The sponsor's reported primary analysis is a two-sided t-test of the mean difference (net). It estimates the difference as -2.88, with a 95% confidence interval from -3.42 to -2.33, and reports p < 0.001. The direction indicates a lower mean pain score for Belotero Balance with integral lidocaine than for Belotero Balance without lidocaine in the posted results.

The simple unadjusted re-calculation from the posted summary statistics estimates the difference as -2.87, with a 95% confidence interval from -3.701 to -2.039 and p < 0.001. The estimates agree closely in direction and approximate magnitude, though their intervals and p-value reporting differ. The registry record does not flag a discrepancy.

The re-calculation is limited to the posted means, standard deviations, and sample counts. It does not recreate participant-level pairing or any other analysis detail not reported in the registry record. The sponsor's own analysis is therefore the reported trial analysis; the re-calculation is a separate, simple summary-statistic comparison, not a correction to the sponsor's result.

15. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary outcomes in addition to the primary pain endpoint. It does not report whether the study used a multiplicity procedure, a prespecified testing hierarchy, or another method to control the interpretation of multiple statistical tests. Without that information, the posted unadjusted secondary p-values should be read as individual comparisons rather than as results adjusted for the full set of outcomes.

The primary analysis population is identified as the full analysis set. It included all randomized participants, analyzed as randomized. This gives a stated population for the primary endpoint, but the registry record does not report further details about how missing primary assessments were handled or whether any sensitivity analyses were performed.

The primary outcome has 52 observations for each product, matching the recorded enrollment of 52 in the split-face design. For the Week 6 responder outcome, the posted denominators are 51 for each product. The reason the denominator is not 52 is not reported in the registry record. The record does not state whether the difference reflects missing assessments, an analysis-population rule, or another reason, so none should be assumed.

For other secondary outcomes, the registry record lists outcomes that do not have posted results in the available record. Reasons for absent results are not reported in the registry record. The original sample-size justification, interim analyses, and complete statistical analysis plan are also not reported. These omissions limit assessment of analysis choices and of whether all planned outcomes are represented, but they do not alter the numerical results that are posted.

16. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The registry reports safety figures for the combined group titled Belotero Balance with or without lidocaine. Among 52 participants at risk, 0 were affected by serious adverse events, and the death count was 0. The record also lists 5 participants with other adverse events among 52 at risk.

These are participant counts for the recorded safety group. They do not provide a product-specific comparison, and the registry record does not report event descriptions for the serious-event category. The list of serious-event terms is empty, alongside the reported count of 0 participants affected. The record does not provide further detail about event timing, severity beyond the serious classification, relatedness, or how the other adverse events were distributed between products.

In general, a count of zero serious events in a study does not establish that an event cannot occur; it describes what was recorded among the participants observed. Safety counts should be interpreted in light of the size and duration of the study and the completeness of reporting. The record's safety summary covers this trial's recorded participants and does not support broader conclusions beyond those data.

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

The posted primary result shows a lower mean immediate VAS pain score for Belotero Balance with integral lidocaine than for Belotero Balance without lidocaine. The sponsor-reported mean difference is -2.88, with a 95% confidence interval from -3.42 to -2.33. The re-calculated unadjusted estimate is -2.87, with its own 95% confidence interval. These estimates describe group averages for the Day 1 assessment immediately after injection.

The result does not mean that every participant had a lower score with the test product. Group means do not reveal each person's paired scores or the full distribution of individual experiences. Nor does an immediate post-injection pain score measure pain later in the study, the appearance of the folds, or the duration of a treatment response.

The study's split-face design means both products were assessed within each participant, with treatment side randomized. That structure can support a within-person comparison, but the registry record does not report the participant-level data or enough detail to determine exactly how the reported test handled the pairing. The re-calculation based on posted summary statistics is unadjusted and should not be confused with a full paired analysis.

The result also does not establish the clinical importance of the estimated difference. The registry record does not report a threshold for a meaningful VAS change. Statistical significance and clinical importance are distinct questions: a test can indicate evidence of a difference without defining whether its magnitude matters to participants.

Finally, the posted secondary and safety data concern different outcomes and do not provide a complete account of every listed secondary measure. The primary finding should therefore be understood narrowly as a comparison of immediate pain scores under the conditions recorded in this completed trial.

18. Why This Trial Matters Statistically

This trial illustrates how design and analysis must be read together. A split-face comparison places both products within the same participant and randomizes which side receives each one. In general, this design can make within-participant comparisons informative, but it also means the two observations are related. A summary-statistic re-calculation that does not preserve pairing may not reproduce the uncertainty calculation from an analysis using participant-level data.

The distinction between a sponsor-reported analysis and a simple re-calculation is important for transparent interpretation. Here, the registry reports the sponsor's two-sided t-test and a mean difference with a confidence interval. A separate unadjusted re-calculation gives a similar estimated direction and magnitude, while its confidence interval differs. Those results should be understood as related but methodologically distinct summaries.

The trial also shows why statistical significance should not be treated as a complete interpretation. The primary estimate and its interval describe the size and precision of a difference in immediate pain scores. They do not define clinical importance, represent every participant's experience, or answer questions about outcomes at other times.

Finally, secondary outcomes, missing result entries, and limited safety detail all affect the scope of interpretation. Reporting which analyses are available—and which planning or analysis details are not reported—helps readers distinguish evidence in the registry record from assumptions that cannot be verified from it.

19. Limitations

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

The registry record does not report the original sample-size justification or the trial's own planning assumptions. The sample-size illustrations based on observed effects cannot fill that gap or establish how the study was designed to achieve its enrollment.

Although the record labels the study randomized, triple-masked, and parallel, it also describes a split-face design with treatment side randomized. Further detail explaining the relationship between the parallel-model label and the split-face allocation is not reported in the registry record. The record does not describe which people were masked or how masking was maintained.

The registry reports a two-sided t-test for the sponsor's primary analysis, but does not give enough detail to establish whether the analysis accounted for the pairing of folds within participants. Participant-level scores and paired differences are not reported. The unadjusted re-calculation from summary statistics therefore cannot verify the sponsor's implementation.

The Week 6 responder outcome has 51 observations per product, while the primary outcome has 52. The reason for the difference and the missing-data handling are not reported in the registry record. Some listed secondary outcomes have no posted results, and the reasons are also not reported. Multiplicity procedures and a complete analysis plan are not reported.

The available safety summary combines participants under a group title covering products with or without lidocaine. It does not provide a product-specific comparison or detailed event descriptions. These reporting limits constrain interpretation of secondary outcomes and safety, even while the primary pain result is numerically reported.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Evaluation of Pain With Belotero® Balance With Integral Lidocaine for Correction of the Nasolabial Folds — NCT03319719.
• Registry record last updated 2019-10-01; status last verified 2018-01.
• Results first posted 2019-10-01.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

NCT03319719 is a completed randomized, triple-masked study sponsored by Merz North America, Inc. It enrolled 52 participants for correction of moderate to severe nasolabial folds. The registry describes a split-face design in which Belotero Balance with integral lidocaine and Belotero Balance without lidocaine were injected into opposite folds, with treatment side randomized.

The primary outcome was mean VAS pain immediately after injection on Day 1. The sponsor reported a mean difference (net) of -2.88, with a 95% confidence interval from -3.42 to -2.33. The simple unadjusted re-calculation was -2.87, with a 95% confidence interval from -3.701 to -2.039.

The registry also lists secondary outcomes and safety measures, but results are not posted for every listed secondary outcome. Original sample-size assumptions, detailed missing-data methods, and a full statistical analysis plan are not reported in the registry record.