透明质酸填充剂 CPM-V ± 利多卡因颏部塑形：随机多中心研究

Abstract 原文摘要

BackgroundThis post-marketing study evaluated the clinical performance and safety of Belotero ® Volume (CPM-V) and Belotero ® Volume Lidocaine (CPM-V+) for chin augmentation in a real-world setting.

MethodsThis prospective, open-label, randomized study was carried out in Germany. Participants seeking chin augmentation received treatment with CPM-V (n=58) or CPM-V+ (n=63), with an optional touch-up 4 weeks after. The primary effectiveness endpoint was change in chin volume (mL) from baseline to 12 weeks after the last injection (Week 12 or Week 16 for participants with touch-up treatment), measured by validated 3D facial imaging. Secondary endpoints included the change from baseline in the glabella-subnasale-pogonion (G-Sn-Pg) angle (°), the investigator- and participant-assessed Global Aesthetic Improvement Scales (iGAIS/pGAIS) scores, the investigator-assessed Merz Aesthetics Scale (MAS) for chin projection, and participant satisfaction with treatment evaluated by FACE-Q – Satisfaction with Chin. Safety was assessed through adverse event reporting.

ResultsFrom baseline to Week 12/16, chin volume increased by a mean (standard deviation [SD]) of 2.5 (0.2) mL (95% confidence interval 2.1, 2.9; p<0.0001) and mean (SD) G-Sn-Pg angle increased by 1.9° (1.7°). At Week 12/16, almost all participants experienced ≥1 point improvements from baseline in MAS for chin projection (91.4%), iGAIS (100%), and pGAIS (99.1%). The mean (SD) Rasch-transformed score FACE-Q – Satisfaction with Chin was 66.6 (18.7) at Week 12/16. Thirty participants (24.8%) reported treatment-related adverse events; incidence was similar between treatment groups and the majority of events were mild to moderate in intensity and transient in nature.

ConclusionCPM-V and CPM-V+ were effective for chin augmentation in aesthetic clinical practice. No new safety concerns were identified.

Keywords: hyaluronic acid filler、dermal filler、chin augmentation、HA、Belotero volume、CPM-V

Introduction

In an aesthetically pleasing, well-balanced face, the chin and its projection is an important component of attractiveness, contributing to the standard of beauty for women and men. 1 , 2 As well as affecting the overall aesthetic harmony of a face, a retrusive or “weak” chin can affect an individual’s perception of their own attractiveness and impact their psychosocial wellbeing. 1–3 Congenital factors are a key determinant in chin morphology, with aging also contributing to a retrusive appearance through skin slackness and reduced mandibular height and length due to increased bone resorption. 3 , 4

Surgical correction of chin retrusion through chin augmentation, or mentoplasty, is relatively common, with approximately 5500 procedures carried out each year in the US. 5 Alternatively, for individuals with mild to moderate retrusion (<10 mm), dermal fillers offer a nonsurgical, temporary correction of chin retrusion through increased volume and reshaping. 4 Fillers used for nonsurgical aesthetic treatment include calcium hydroxylapatite, poly-L-lactic acid and hyaluronic acid (HA). 6

As the soft tissues of the chin adhere tightly to the bone, HA-based fillers with a high lifting capacity (high G prime) are often preferred for chin augmentation. 6 In comparison with HA gels designed for the correction of wrinkles and folds, high G prime fillers are typically more cohesive and able to oppose deformation and flattening, thus maintaining their shape over time. 6 , 7

CPM-V (Belotero ® Volume) and CPM-V+ (Belotero ® Volume Lidocaine; both Anteis S.A., Plan-les-Ouates, Switzerland, a company of the Merz Aesthetics group) are high G prime cohesive polydensified matrix (CPM) HA-based dermal fillers used for chin augmentation.

This is the first study to assess the clinical performance and safety of CPM-V and CPM-V+ in participants seeking chin augmentation. Uniquely, this study combined a real-world design with 3D imaging techniques and subjective, validated scales to collect comprehensive data on the acceptability of the treatment’s duration.

Materials and Methods

Study Design

This was a prospective, open-label, multicenter, randomized, parallel-group, post-marketing clinical investigation conducted at 11 sites in Germany. The study was performed in accordance with ISO 14155, and Medical Device (MEDDEV) guidance 2.12/2 and MEDDEV 2.7/1 revision 4; compliance with these requirements constituted conformity with the ethical principles of the Declaration of Helsinki. All relevant study-related documents, including the clinical investigation plan, were reviewed and approved by an independent ethics committee. All participants provided written informed consent.

Figure 1 provides an overview of the study design and visit schedule. After an initial screening period, baseline clinical assessments were performed on Day 1, followed by randomization and treatment. At Week 4, an optional touch-up treatment was performed, if deemed necessary by the investigator and participant. The duration of the investigation was 48 weeks for participants without touch-up treatment and 52 weeks for participants with touch-up treatment.


Figure 1 Study design and visit schedule.

Participants

Eligible participants were male or female ≥18 years old, whose initial chin treatment required at least 2 mL CPM-V or CPM-V+ at the baseline visit. Participants were required to have a glabella-subnasale-pogonion angle (G-Sn-Pg) of 155° to 170° at the screening visit and be willing to abstain from any other facial procedures (eg., dermal fillers outside of this clinical investigation, toxin treatments, facial ablative or fractional laser, microdermabrasion, chemical peels, noninvasive skin tightening, and surgical procedures) during the study.

Participants with severe microgenia, actinic damaged skin, and/or premature skin aging in the treatment area were excluded. Participants with a history of treatment with silicone, polymethyl methacrylate, fat injections, poly L-lactic acid, chin implants or other permanent dermal fillers below the nose were also excluded.

Randomization

Participants were randomly assigned to CPM-V or CPM-V+ in a 1:1 ratio and stratified by site using block randomization.

Treatment

CPM-V and CPM-V+ are transparent cross-linked sodium hyaluronate gels of non-animal origin suspended in a physiological phosphate buffer and were provided in single use prefilled sterile glass syringes. Both treatments are CE-approved in the EU and were provided by Merz Aesthetics GmbH (Frankfurt am Main, Hessen, Germany); participants received all study treatment free of charge. Both treatments contain 26 mg/mL HA in a sodium phosphate buffer. CPM-V+ also contains 3 mg/mL of lidocaine hydrochloride. Injection volume (mL), depth and technique were individualized at the investigator’s judgment, based on participant expectations, anatomy, and safety considerations. All initial treatment volumes were ≥2 mL and the total volume administered per participant (inclusive of the initial and touch-up treatment) was limited to 5 mL.

At baseline, a single treatment was applied by the treating investigator in the chin area, with an optional touch-up treatment 4 weeks after. The borders of the region of interest of the treated chin area were defined by the five anatomical landmarks shown in Supplementary Figure S1.

Assessments

The change in volume of the chin region of interest and chin projection relative to baseline were assessed using validated 3D facial imaging (QuantifiCare S.A., Biot, France). Using the 3D images, the volume change and G-Sn-Pg angle were measured with QuantifiCare software (Supplementary Figure S2).

The validated Merz Aesthetics Scale (MAS) was used to assess chin projection; 8 MAS is a 5-point scale ranging from 0 (full chin projection) to 4 (very severe chin retrusion) and was completed by the investigator.

Participants’ global aesthetic improvement was assessed using the investigator- and participant-assessed Global Aesthetic Improvement Scales (iGAIS and pGAIS, respectively). The treating investigator and participant performed live ratings using baseline 2D photographs for comparison. Both scales have seven scoring categories, ranging from +3 (very much improved) to −3 (very much worse).

Participant satisfaction with treatment was evaluated using validated FACE-Q instruments. 9 , 10 The FACE-Q – Satisfaction with Chin is a 10-item scale with statements regarding the appearance (size, width and shape) of the participants’ chin. The FACE-Q – Satisfaction with Lower Face and Jawline is a 5-item scale with statements regarding the appearance of the participants’ jawline. FACE-Q assessments over time were measured using absolute Rasch-transformed FACE-Q scores (scores ranged from 0 [worst] to 100 [best]).

Endpoints

The primary effectiveness endpoint was the change in chin volume from baseline to 12 weeks after the last injection (Week 12/16 for participants without/with touch-up treatment, respectively), as measured by the validated 3D facial imaging method for volume assessment.

The secondary effectiveness endpoints, all assessed 12 weeks after the last injection, were the change from baseline in G-Sn-Pg angle, the response rate on the MAS for chin projection (response defined as ≥1-point improvement from baseline), iGAIS, and pGAIS, and change from baseline in Rasch-transformed FACE-Q scores.

Other effectiveness endpoints included the time course of chin volume change from baseline, G-Sn-Pg angle, G-Sn-Pg angle change from baseline, and Rasch-transformed FACE-Q scores (absolute scores and change from baseline).

Safety endpoints included the incidence of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs. The extent of exposure, injection techniques, and depth of injection were also recorded.

Statistical Analysis

The primary effectiveness analysis was assessed using data pooled from both the CPM-V and CPM-V+ treatment groups, using the full analysis set (FAS), which was defined as all randomized participants. Missing values were imputed using multiple imputation. Further effectiveness analyses based on observed cases in the FAS were performed by treatment group (CPM-V or CPM-V+) and also for the pooled treatment group. Safety analyses were carried out by treatment group and for the pooled treatment group on the safety evaluation set, defined as all participants who were exposed to study medication at least once.

For the primary effectiveness analysis, the mean change in chin volume from baseline to 12 weeks after the last injection was analyzed using a two-sided one-sample t -test and corresponding 95% Wald confidence interval (CI). Based on the power calculation for the primary effectiveness endpoint, effectiveness was concluded if the lower bound of the two-sided 95% CI exceeded the pre-defined threshold of 1.0 mL. No covariate adjustment was performed, as the enrolled population was expected to be representative of the target population. Additional sensitivity analyses were performed on observed cases in the per protocol set (PPS) of participants (participants without any major protocol deviations), and the FAS. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina, USA).

Results

Study Participants

Overall, 121 participants were randomly assigned to CPM-V (n=58, 47.9%) or CPM-V+ (n=63, 52.1%). Of these, 112 participants completed the clinical investigation; participant disposition is shown in Figure 2 .

Participant demographics are provided in Table 1 . Most participants were female (n=112; 92.6%) and White (n=114; 94.2%). The mean age was 44.5 years (range 21–73 years) and the most common Fitzpatrick skin types were III (n=52; 43.0%) and II (n=49; 40.5%).

Table 1 Summary of Participant Demographics

The overall mean (standard deviation [SD]) injection volume was 3.33 (1.065) mL (range 2.0–5.0 mL). The mean (SD) injection volume was 2.64 (0.917) mL (range 2.0–5.0 mL) for the initial treatment and 1.21 (0.644) mL (range 0.2–3.0 mL) for touch-up treatment. The injection techniques used were bolus/depot, serial puncture, fanning, and linear threading retrograde. Of these techniques, bolus/depot injection was the most common at both baseline (n=79; 65.3%) and Week 4 (n=51; 73.9%). At baseline, the most frequently used instruments for administering treatment were the 27G 12.7 mm needle (n=81; 66.9%) and the 27G 37 mm cannula (n=32; 26.4%). At Week 4, the 27G 12.7 mm needle (n=48; 69.6%) and the 30G 12.7 mm needle (n=14; 20.3%) were the most commonly used instruments.

Participants received injections either into the subcutaneous or supraperiosteal layer (or both). Most participants received treatment in the supraperiosteal layer at baseline (n=117; 96.7%), and at Week 4 (n=62; 89.9%). Fewer participants received treatment in the subcutaneous layer at baseline (n=80; 66.1%), and at Week 4 (n=38; 55.1%).


Figure 2 Participant disposition.

Chin Volume Augmentation

For the primary endpoint analysis, data were available for 104 (86.0%) participants in the FAS population, with missing data imputed for the remaining 17 (14.0%) participants. The estimated average of the mean (SD) increase in chin volume from baseline to Week 12/16 was 2.49 (0.183) mL (95% CI 2.13, 2.85; p<0.0001) for the pooled treatment group, demonstrating a statistically significant increase above the target threshold of 1.00 mL ( Table 2 ).

Table 2 Change in Chin Volume from Baseline to Week 12/16

Results were confirmed through sensitivity analyses performed on observed cases in the PPS and FAS. The mean (SD) increase in chin volume from baseline to Week 12/16 was similar in the PPS (2.42 [1.668] mL; 95% CI 2.08, 2.76; p<0.0001) and FAS populations (2.50 [1.867] mL; 95% CI 2.14, 2.86; p<0.0001).

Change in Chin Volume Over Time (Observed Cases)

The mean increase in chin volume from baseline was comparable between treatment groups at all timepoints. In the combined treatment group and based on observed cases in the FAS, participants had a mean (SD) increase in chin volume from baseline of 2.70 (1.735) mL at Week 4; 2.50 (1.867) mL at Week 12/16; 2.29 (1.843) mL at Week 24/28; 2.05 (1.720) mL at Week 36/40, and 1.86 (1.658) mL at Week 48/52 ( Figure 3 ).


Figure 3 Change from baseline in chin volume by study visit. Analysis based on observed cases in the FAS. Weeks 16, 28, 40 and 52 apply to participants with optional touch-up treatment at Week 4. Error bars represent standard deviation.

G-Sn-Pg Angle Change from Baseline

Mean G-Sn-Pg angles increased after treatment in comparison with baseline ( Table 3 and Figure 4 ). While G-Sn-Pg angles decreased over the course of the study, at Week 48/52 they remained higher than baseline ( Figure 4 ). At baseline, the mean (SD) G-Sn-Pg angle was 162.04° (3.811) in the pooled treatment group, which increased to 163.87° (3.384) at Week 12/16. By Week 48/52, the mean (SD) angle reduced slightly to 163.46° (3.658). In the pooled treatment group, the overall mean (SD) increase G-Sn-Pg angle from baseline was 1.89° (1.645) at Week 12/16 and 1.51° (1.452) at Week 48/52.

Table 3 G-Sn-Pg Angle and Change from Baseline to Week 12/16


Figure 4 G-Sn-Pg angle by study visit. Analysis based on observed cases in the FAS. Weeks 16, 28, 40 and 52 apply to participants with optional touch-up treatment at Week 4. Error bars represent standard deviation.

MAS Scores for Chin Projection

Most participants experienced an improvement of one point or more on the MAS for chin projection, with a responder rate of 91.4% at Week 12/16. The mean (SD) MAS score for chin projection at baseline was 2.3 (0.76) and decreased to 0.7 (0.64) at Week 12/16.

iGAIS and pGAIS

All participants (100%) had an improvement in iGAIS (score ≥1 from baseline) at Week 12/16, with most participants scoring +2 “much improved” (62.9%; n/participants with observed cases [N-obs]=73/116), followed by +3 “very much improved” (19.8%; n/N-obs=23/116), and +1 “improved” (17.2%; n/N-obs: 20/116).

Similarly, almost all participants (99.1%) had an improvement in pGAIS (score of ≥1 from baseline) at Week 12/16. Most participants scored themselves +2 “much improved” (46.6%; n/N-obs=54/116), followed by +1 “improved” (40.5%; n/N-obs=47/116), and +3 “very much improved” (12.1%; n/N-obs=14/116). One participant (0.9%) scored themself −2 “much worse”.

Representative 2D participant photographs at baseline and Weeks 4, 12, and 48 are provided in Figure 5 . Representative 3D before and after participant photographs are provided in Video S1.


Figure 5 Representative 2D participant photographs. Representative photographs of a 28-year old male participant at (A) baseline, (B) Week 16 (12 weeks after last injection), (C) Week 4, and (D) Week 52. The participant received 4 mL CPM-V+ treatment at baseline and 1 mL at Week 4 (touch-up). MAS score at baseline was 2 (moderate chin retrusion) and 0 (full chin projection) at all subsequent timepoints. At Week 16 (B), the total change from baseline in chin volume was +7.20 mL.

FACE-Q

For FACE-Q – Satisfaction with Chin, the mean (SD) Rasch-transformed score was 66.6 (18.7) at Week 12/16, representing a mean change from baseline of +29.2 (20.8). At Week 48/52, the mean (SD) score was 57.0 (18.3). For FACE-Q – Satisfaction with Lower Face and Jawline, the mean (SD) score was 30.4 (17.1) at baseline, 65.6 (18.1) at Week 12/16, and 53.5 (21.1) at Week 48/52.

Safety

Overall, 68 participants (56.2%) reported a TEAE. Thirty participants (24.8%) reported treatment-related TEAEs; the number of related TEAEs was comparable in both treatment groups ( Table 4 ). The most common related TEAEs were injection-site hematoma in 19 participants (15.7%), injection-site pain in 13 participants (10.7%), injection-site swelling in 11 participants (9.1%), and injection-site erythema in six participants (5.0%). Other related TEAEs occurring in at least one participant included injection-site nodule, hypoesthesia, and pruritus in 5 (4.1%), 3 (2.5%) and 3 (2.5%) participants, respectively.

Table 4 Summary of Treatment-Emergent Adverse Events

Overall, 19 participants (15.7%) reported mild related TEAEs, and nine (7.4%) reported moderate related TEAEs. Two participants (1.7%) reported severe related TEAEs; both were injection-site hematoma, which lasted for 17 days in one participant and 8 days in the other. The majority of related TEAEs were considered transient and fully resolved by the end of the study. No related TEAEs leading to study discontinuation were reported.

Discussion

The results from this post-marketing clinical study confirm the clinical performance and safety of CPM-V and CPM-V+ for chin augmentation, under real-world conditions. The study met its primary endpoint, with an estimated mean increase in chin volume of 2.49 mL (95% CI 2.13, 2.85) over all imputations at 12 weeks after last injection, which significantly exceeded the target threshold of 1.00 mL.

In our study, the primary effectiveness endpoint was assessed using an objective, validated 3D imaging approach. Within our study, sensitivity and subgroup analyses showed consistent results, supporting the robustness of this primary effectiveness outcome and confirming that both CPM-V and CPM-V+ deliver a sustained and meaningful improvement in chin volume.

The chin augmentation achieved across treatment arms in the study participants was accompanied by meaningful changes in the facial profile and chin shape, as evidenced by the mean increase in G-Sn-Pg angle by 1.89° at Week 12/16. The improvements in G-Sn-Pg angle observed in this study confirm its clinical utility in assessing changes over time, particularly in real-world practice. Notably, the G-Sn-Pg angle remained elevated in comparison with baseline even at Week 48/52, supporting the durability of treatment effect.

An exceptionally high percentage (>90%) of participants showed improvement and satisfaction on several validated scales, namely the MAS for chin projection, iGAIS, and pGAIS; this was correlated with improved scores on the FACE-Q questionnaires, demonstrating strong investigator and participant satisfaction. The alignment between these scores demonstrates the consistency and reliability of the treatment outcomes.

CPM-V and CPM-V+ were well tolerated; most treatment-related TEAEs were general disorders and mild administration-site conditions. These are to be expected for injection-based treatments and indeed are inherent to dermal filler injections. 11 Despite the inclusion of lidocaine in one of the treatments, the incidence and severity of injection-site reactions did not significantly differ between treatment groups. These findings mirror those from a large systematic review and meta-analysis, which also found no difference in either the effectiveness or safety profile of HA-based dermal fillers with or without lidocaine for the treatment of nasolabial folds. 12

In this study, only two participants reported severe treatment-related TEAEs (both injection-site hematomas), which completely resolved by the end of the study. Rare serious treatment-related TEAEs, such as vascular complications and blindness, 6 , 11 were not reported in this study, however, the risk of serious complications cannot be ignored. Rare complications following chin augmentation with HA-based dermal fillers have been documented in the literature, 13–16 highlighting the importance of training and in-depth knowledge of facial anatomy for all practitioners, regardless of experience level.

The key strengths of this study include the combination of a real-world design with objective 3D imaging techniques and validated scales. This enabled the collection of robust data on treatment acceptability, effectiveness, and duration. The studied population was predominately female (92.6%) and White (94.2%), typical of individuals in Germany seeking aesthetic treatments, therefore these results are highly relevant and informative to real-world practice. Future studies could include a broader ethnic demographic and more male participants to widen the understanding of the treatments’ performance in other groups. Other biases inherent to all open-label, non-controlled studies must also be acknowledged, as well as the risk of subjective bias involved in making effectiveness assessments. Notwithstanding these limitations, the findings reported here reflect real-life conditions in a representative population; therefore, these results are highly relevant, informative, and robust.

Conclusion

The results of this study demonstrated the safety and effectiveness of CPM-V and CPM-V+ for chin augmentation. Validated 3D imaging measurements demonstrated a statistically significant elevation in chin angle 12 weeks following last injection. The primary endpoint was achieved, and the robustness of the augmentation both products achieved was confirmed through sensitivity analyses. At 12 weeks following last injection, all participants showed global aesthetic improvement as assessed by the investigators. High aesthetic improvement rates and participant satisfaction outcomes were maintained throughout the 12-month follow-up period. Both treatments exhibited comparable and favorable safety profiles, and no new safety concerns were identified. These results support the continued use of CPM-V and CPM-V+ for chin augmentation in real-world clinical practice.