Belotero® Intense (+) Lidocaine

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) # I. GENERAL INFORMATION | Device Generic Name: | Injectable Dermal Filler | | --- | --- | | Device Trade Name: | Belotero® Intense (+) Lidocaine | | Device Procode: | LMH | | Applicant's Name and Address: | Merz North America Inc. 6501 Six Forks Road, Raleigh, NC 27615 United States of America | | Date(s) of Panel Recommendation: | None | | Premarket Approval Application (PMA) Number: | P250016 | | Date of FDA Notice of Approval: | July 9, 2026 | # II. INDICATIONS FOR USE Belotero® Intense (+) Lidocaine is indicated for submucosal and/or subcutaneous implantation for lip augmentation in adults over the age of 21. # III. CONTRAINDICATIONS - Belotero® Intense (+) Lidocaine is contraindicated for patients with severe allergies manifested by a history of anaphylaxis or history of multiple severe allergies. - Belotero® Intense (+) Lidocaine contains lidocaine and is contraindicated for patients with known hypersensitivity to lidocaine or anesthetics of the amide type. - Belotero® Intense (+) Lidocaine contains trace amounts of gram-positive bacterial proteins and is contraindicated for patients with a history of allergies to such material. # IV. WARNINGS AND PRECAUTION The warnings and precautions can be found in the Belotero Intense® (+) Lidocaine labeling. # V. DEVICE DESCRIPTION Belotero® Intense (+) Lidocaine is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, colorless, homogenous gel implant. It consists of hyaluronic acid (HA) of non-animal origin, which is crosslinked with BDDE (1,4-butanediol diglycidyl ether) and formulated to a PMA P250016: FDA Summary of Safety and Effectiveness Data 1 of 33 {1} concentration of 25.5 mg/mL with 3.0 mg/mL lidocaine in a physiological phosphate buffer. Belotero® Intense (+) Lidocaine is supplied in a prefilled syringe co-packaged with two sterile 27G 1/2' needles. ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives to achieve lip volume and lip fullness such as other dermal filler products, surgical procedures, implants, or fat injections. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with their physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY Belotero® Intense (+) Lidocaine was first approved for commercial distribution in October 2013 in the European Union (EU). The product was subsequently approved in several countries worldwide and is currently registered and sold in seventy-eight countries outside of the US. Belotero® Intense (+) Lidocaine has not been removed from any marketplace for any reason related to safety or effectiveness. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Potential adverse effects (e.g. complications) associated with the use of the device as reported in the pivotal clinical study at a frequency $\leq 5\%$ of the study participants after initial and touch-up treatment included injection site swelling, induration, pain, discoloration, bruising, erythema, edema, and oral herpes; and after repeat treatment included injection site pain, swelling, bruising, discoloration, and erythema. The common potential adverse effect as reported in the pivotal clinical study at a frequency $> 5\%$ of the study participants included injection site mass. Overall, related AEs were typically mild in intensity, and all resolved without sequelae. There were no serious treatment-related adverse events reported. Additionally, the following rare but serious adverse events that are associated with intravascular injection of other dermal filler material in the face have been reported in the literature: vision impairment (acute or permanent), blindness, cerebral ischemia or cerebral hemorrhage leading to stroke, skin necrosis, and damage to underlying facial structures. The following additional adverse events were observed with similar dermal filler implants and are considered as potential risks for this device: abscess, angioedema, infection, dizziness, fever, hypoesthesia, induration, nausea, numbness, peeling, presyncope, rash, burning sensation, syncope, inflammation, pruritus/itching, swelling, and skin discoloration. For the specific adverse events that occurred in the clinical study, please see Section X below. ---PMA P250016: FDA Summary of Safety and Effectiveness Data 2 of 33 {2} # IX. SUMMARY OF NONCLINICAL STUDIES Belotero® Intense (+) Lidocaine was extensively tested and characterized through physical and chemical testing (Table 1), and biocompatibility studies (Table 2). Preclinical testing results were adequate to support initiation of human clinical studies as a dermal filler. # A. Laboratory Studies The results of non-clinical laboratory studies for Belotero® Intense (+) Lidocaine are summarized in Table 1. Table 1: Physical and Chemical Analyses | Test | Results | | --- | --- | | Appearance | Pass | | pH | Pass | | Osmolarity | Pass | | Mean of Ejection Force | Pass | | Rheological properties: Elastic modulus G' | Pass | | Rheological properties: Tan δ | Pass | | Extractable Volume | Pass | | NaHA Content | Pass | | Lidocaine hydrochloride content | Pass | | 2,6 DMA content | Pass | | Residual BDDE content | Pass | | Endotoxin content | Pass | | Protein content | Pass | Sterilization – Pre-filled syringes are sterilized using a validated moist heat process in a pressurized autoclave. The sterilization cycle is validated according to ISO 17665-1 sterilization standard. The validated sterilization cycle provides a Sterility Assurance Level (SAL) of 10⁻⁶. Stability/Shelf life - Packaged product data has been collected at 25°C/60% relative humidity and was evaluated for conformance to microbiological, physical, and chemical properties. Conformance with all specifications was confirmed. # B. Biocompatibility Studies Belotero® Intense (+) Lidocaine was tested in accordance with ISO 10993 and FDA's biocompatibility guidance "Use of International Standard ISO 10993-1, Biological PMA P250016: FDA Summary of Safety and Effectiveness Data 3 of 33 {3} evaluation of medical devices – Part 1: Evaluation and testing within a risk management” and in compliance with FDA GLP regulations (21 CFR § 58). Test results are summarized in Table 2 Table 2: Summary of Biocompatibility Results | Biological Endpoint | Method | ISO Standard | Results | | --- | --- | --- | --- | | Cytotoxicity | ISO MEM Elution Assay | ISO 10993-5 | Extracts (at 37 °C for 72h in EMEM10 at 0.2 g/mL ratio) gel showed no evidence of cell lysis or cytotoxicity | | Sensitization | ISO Guinea Pig Maximization Sensitization Test | ISO 10993-10 | Non-sensitizing | | Intracutaneous Reactivity/Irritation | ISO Intracutaneous Reactivity / Irritation in rabbits | ISO 10993-23 | Non-irritant Further mitigated using long-term implantation study (minipig) study results which demonstrated no evidence of long-term local intolerance. | | Pyrogenicity | Material Mediated; Bacterial Endotoxin Mediated | USP <151> USP <85> | Non-pyrogenic | | Systemic Toxicity (acute, subacute, subchronic, chronic) & Genotoxicity | Exhaustive Extractable Study Toxicological Risk Assessment | ISO 10993-18 ISO 10993-17 | Chemical characterization of BIL was conducted under exhaustive condition in accordance with the current ISO 10993-18:2020/A1:2022. All reported compounds were assessed as confirmed/ confident/tentative (being the only tentative a hyaluronic acid degradation compound). Toxicological evaluation was performed according to ISO 10993-17:2023 requirements, the latter being recognized by the FDA in December 2023. Under highly conservative worst-case exposure assumptions, all reported compounds demonstrated a Margin of Safety (MOS) greater than 1. Systemic toxicity and genotoxicity risks are considered adequately covered. | PMA P250016: FDA Summary of Safety and Effectiveness Data 4 of 33 {4} | | | | None of the extractables potentially leaching out of the product is considered to pose an undue risk to the patient under intended clinical use | | --- | --- | --- | --- | | Implantation/ Chronic Local Tissue and Degradation Effects | 167-Week Implantation study in a mini-pig model | ISO 10993-6 | Local Tissue Effects: Non-irritant In vivo Degradation: These advanced levels of article degradation, together with the minimal local tissue reaction observed at the last time point of 167 weeks (steady-state) are compatible with the late time frame as per the ISO 10993-6 standard | Carcinogenicity risks: The excess cancer risks for Belotero® Intense (+) Lidocaine are in the same range of acceptable cancer risks as other previously approved dermal filler products. ## X. **SUMMARY OF PRIMARY CLINICAL STUDY** The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of Belotero® Intense (+) Lidocaine dermal filler for lip augmentation in adults over the age of 21 in the US under IDE G220271. Data from this clinical study was the basis for the PMA approval decision. A summary of the clinical study is presented below. ### A. **Study Design** Participants were treated between 07-MAR-2023 and 08-JUL-2024. The database for this PMA reflected data collected through 26-SEP-2024 and included 220 treated participants (165 treated with Belotero® Intense (+) Lidocaine and 55 treated with an FDA-approved comparator product). There were 14 investigational sites and 13 of these 14 investigational sites enrolled participants. The study was a multicenter, evaluator-blinded, randomized, comparator-controlled pivotal clinical study to evaluate the safety and effectiveness of Belotero® Intense (+) Lidocaine versus an FDA-approved comparator product for injection into the lips. The control group was a legally marketed alternative with similar indications for use. A total of 220 participants were randomized and received treatment with either Belotero® Intense (+) Lidocaine (n=165) or comparator (n=55) at the outset of the study. An optional touch-up treatment was performed approximately 4 weeks after the initial treatment, if deemed necessary, to achieve optimal correction. PMA P250016: FDA Summary of Safety and Effectiveness Data 5 of 33 {5} # 1. Clinical Inclusion and Exclusion Criteria Enrollment in the clinical study was limited to participants who met the following inclusion criteria. - A) Participant of FST I to IV who desired lip augmentation to correct volume deficit and had upper and lower lip deficit with a rating of 0 (very thin), 1 (thin), or 2 (medium) on the Merz Lip Fullness Assessment Scale (MLFAS), as determined independently by the treating investigator and the blinded evaluator. B) Participant of FST V or VI who desired lip augmentation to correct volume deficit and had upper and/or lower lip deficit with a rating of 0 (very thin), 1 (thin), or 2 (medium) on the MLFAS, as determined independently by the treating investigator and the blinded evaluator. - Female or male who was ≥21 and ≤65 years of age at screening. - Had an adequate understanding (reading, speaking, and writing) of the English language. Participants were not permitted to enroll in the clinical study if they met any of the following exclusion criteria: - Received treatments with porcine-based collagen fillers or with Juvéderm® Voluma XC, Restylane® Lyft Lidocaine, or calcium hydroxylapatite (CaHA), within the past 24 months and/or with other dermal HA fillers within the past 12 months in the lips, in the lower third of the face, and/or the nose or planned to receive such treatments in the face during the study. - Prior treatment with dermal therapies (e.g., facial ablative or fractional laser, microdermabrasion, chemical peels, noninvasive skin tightening) within the past three months in the lower third of the face, including the nose, that could interfere with effectiveness assessments. - Undergone oral surgery (e.g., orthodontia, extraction, implants) in the past 30 days or planned to undergo oral surgery during the study. - Lip volume deficit due to a medical condition, such as a congenital defect, trauma, abnormalities in adipose tissue related to immune-mediated disease, such as generalized lipodystrophy (i.e., juvenile dermatomyositis), partial lipodystrophy (i.e., Barraquer-Simons Syndrome), inherited disease, or human immunodeficiency virus (HIV)-related disease. - Abnormal lip function, with inability to effectively suck water through a straw. - Abnormal lip sensation, with inability to feel a 0.4 g monofilament or a cotton wisp at any site on the lip. - Moderate or severe abnormal lip asymmetry. PMA P250016: FDA Summary of Safety and Effectiveness Data 6 of 33 {6} - Acute inflammatory process or active infection at the injection site (e.g., skin eruptions, such as cold scores, cysts, pimples, acne, eczema, rashes, hives, abscess, or Streptococcus infection) or had a history of chronic or recurrent infection or inflammation with the potential to interfere with the study results or increase the risk of AEs. ## 2. Follow-up Schedule All participants were scheduled to return for follow-up in-clinic examinations at 2, 4, 8, 16, 24, 36 and 48 weeks after the last treatment (initial or touch-up) postoperatively. Participants who received a touch-up treatment at Week 4 also had a safety follow up visit at Week 6 and Week 8. At 48 weeks after last treatment, participants randomized to initial treatment with Belotero® Intense (+) Lidocaine treatment were eligible for an optional repeat treatment, with post repeat treatment follow-up period of additional 12 weeks, for a total study duration of up to 64 weeks. If repeat treatment was performed, in-person safety assessments were scheduled 2 and 4 weeks post repeat treatment. Participants treated with comparator were followed for 48 weeks post-last treatment (i.e., initial or applicable touchup), for a total study duration of up to 52 weeks. Preoperatively, the following evaluations were performed: pregnancy test (for females of childbearing potential), height and weight measurements for body mass index (BMI), FACE-Q assessments (satisfaction with lips, psychological function), blinded evaluator MLFAS assessment, treating investigator MLFAS assessment, lip function / sensation assessments, lip symmetry and movement questionnaire, lip hydration and appearance questionnaire, and visual safety assessments (visual acuity test, confrontation visual field test, ocular motility test and retinal photography). **Table 3** provides the objective parameters that were assessed during the study. Adverse events and complications were recorded at all visits during the study. **Table 3: Objective Assessments Performed During the Study** | | Visit Timepoint | Safety Assessments | Effectiveness Assessments | | --- | --- | --- | --- | | Day 1 / Baseline | **Initial treatment** | Visual safety assessments CTR diary AEs | N/A | | | Up to 72h after treatment | CTR diary AEs | N/A | | | 2 weeks after treatment | Visual safety assessments Lip function / sensation assessments CTR diary AEs | N/A | PMA P250016: FDA Summary of Safety and Effectiveness Data 7 of 33 {7} | Optional touch-up treatment | **Week 4** post-initial treatment | Visual safety assessments Lip function / sensation assessments CTR diary AEs | Merz Lip Fullness Assessment Scale (MLFAS) | | --- | --- | --- | --- | | | Up to 72h after treatment^{1} | CTR diary AEs | N/A | | | 2 weeks after treatment^{1} | Visual safety assessments Lip function / sensation assessments CTR diary AEs | N/A | | | 4 weeks after treatment^{1} | Visual safety assessments Lip function / sensation assessments CTR diary AEs | N/A | | Primary Endpoint assessment | **Week 8** post-last treatment | Visual safety assessments Lip function / sensation assessments AEs | MLFAS, investigator Global Aesthetic Improvement Scale (iGAIS), subject Global Aesthetic Improvement Scale (sGAIS), and Face-Q questionnaires | | Maintenance Phase | **Week 16** post-last treatment | Visual safety assessments Lip function / sensation assessments AEs | MLFAS, iGAIS, sGAIS, and Face-Q | | Maintenance Phase | **Week 24** post-last treatment | Lip function / sensation assessments AEs | MLFAS, iGAIS, sGAIS, and Face-Q | | Maintenance Phase | **Week 36** post-last treatment | Lip function / sensation assessments AEs | MLFAS, iGAIS, sGAIS, and Face-Q | | Optional retreatment^{2} | **Week 48** post-last treatment | Visual safety assessments Lip function / sensation assessments AEs | MLFAS, iGAIS, sGAIS, and Face-Q | | | Up to 72h after retreatment^{1} | CTR diary AEs | N/A | | | 2 weeks after retreatment^{1} | Visual safety assessments Lip function / sensation assessments CTR diary AEs | N/A | | | 4 weeks after retreatment^{1} | Visual safety assessments Lip function / sensation assessments CTR diary AEs | N/A | PMA P250016: FDA Summary of Safety and Effectiveness Data 8 of 33 {8} | Retreatment Phase | Week 60 post-initial treatment / touch-up or 12 weeks post retreatment | Visual safety assessments Lip function / sensation assessments CTR diary AEs | MLFAS, iGAIS, sGAIS, Face-Q and likelihood of retreatment survey | | --- | --- | --- | --- | ¹ Safety follow up assessments were only for participants who received a touch-up at Week 4. ² Optional retreatment was only offered to participants in the Belotero® Intense (+) Lidocaine treatment groups. ³ Safety follow up assessments were only for participants who received optional retreatment at Week 48 post-initial treatment. All participants received a safety follow-up phone call 72 hours after each treatment (i.e., initial, touch up, optional retreatment). The treating investigator determined the appropriate volume of Belotero® Intense (+) Lidocaine or comparator product to be injected in the lips (injection volumes did not exceed 6 mL (3 mL per lip) for initial and touch-up treatment combined, and another 3 mL for Belotero® Intense (+) Lidocaine repeat treatment. Participants were in the Belotero® Intense (+) Lidocaine group received treatment in the lips with the co-packaged 27G ½" needles. The key timepoints are shown below in the tables summarizing safety and effectiveness. ### 3. Clinical Endpoints Belotero® Intense (+) Lidocaine was injected into the subcutaneous and/or submucosal plane. A tunneling technique, fanning technique, or a combination was used to achieve optimal results. The overall total median volume of Belotero® Intense (+) Lidocaine injected to achieve optimal aesthetic outcome was 1.6 mL during initial/touch-up treatment. Participants received a median volume of 0.8 mL in the upper lip, 0.8 mL in the lower lip. Injection volumes into the lips after repeat treatment tended to be lower, with the typical total median injection volume to achieve optimal correction after repeat treatment being approximately 0.9 mL. Similar injection volumes were used in participants treated with the comparator device. With regards to safety, the following endpoints were evaluated: - Incidence of related serious adverse events (SAEs) or related delayed-onset AEs (> 21 days after last treatment) following the first treatment including touch-up until Week 48, - Incidence of any AEs, SAEs, related AEs, and AEs leading to discontinuation, - Incidence of related serious adverse events (SAEs) or related delayed-onset AEs (> 21 days after last treatment) following repeat treatment from Week 48 to Week 60 for participants retreated with Belotero® Intense (+) Lidocaine and not retreated, - Incidence, severity, and duration of common treatment responses (CTRs) reported in participant diaries for 28 days following each injection. PMA P250016: FDA Summary of Safety and Effectiveness Data 9 of 33 {9} With regards to effectiveness, the primary effectiveness endpoint was the mean change from baseline to Week 8 post last injection in mean lip fullness as assessed live by the blinded evaluator using the validated 5-point MLFAS. The co-primary effectiveness endpoint was the responder rate at Week 8 post last injection according to the MLFAS, as assessed live by blinded evaluator. Responders were defined as participants with ≥ 1-point MLFAS improvement compared to baseline on treated lip(s). For participants with both lips treated, each lip was required to demonstrate ≥1-point MLFAS improvement from baseline for the participant to qualify as a responder. The primary objective of the study was to demonstrate that the response rate in the Belotero® Intense (+) Lidocaine group is statistically significantly larger than 50% and to demonstrate noninferiority of Belotero® Intense (+) Lidocaine over comparator control in mean change from baseline in MLFAS with a pre-specified non-inferiority margin of -0.5 and a significance level of one-sided 0.025. With regard to success/failure criteria, effectiveness of Belotero® Intense (+) Lidocaine at Week 8 (post-initial or touch-up injection) was demonstrated if the change from baseline in the treatment group was statistically non-inferior to that of the comparator group. The analysis was based on the average MLFAS scores of both lips for each participant, if both lips were treated. A baseline-adjusted analysis of covariance (ANCOVA) model was applied, including treatment group, study site, and Fitzpatrick Skin Type as fixed effects and baseline MLFAS as a covariate, to estimate the treatment difference and its corresponding confidence interval. Non-inferiority was assessed at a one-sided significance level of 2.5%, corresponding to a two-sided 95% confidence interval. The null hypothesis of inferiority was rejected if the lower bound of the 95% confidence interval for the difference in mean change from baseline (treatment minus comparator) exceeded the non-inferiority margin of -0.5. Success for the co-primary effectiveness endpoint was achieved if the proportion of responders at Week 8 (after the initial and/or touch-up injection) was statistically greater than 50%. The null hypothesis of a responder rate ≤ 50% was rejected if the lower bound of the exact two-sided 95% confidence interval for the responder rate, based on a binomial distribution, exceeded the pre-defined threshold of 50%. Both success criteria for the primary and co-primary effectiveness endpoints had to be met to conclude overall effectiveness of Belotero® Intense (+) Lidocaine. Hypotheses and analysis methods were pre-specified for both endpoints. The one-sided family-wise type I error rate (α = 2.5%) was controlled using a hierarchical testing procedure. Specifically, the primary endpoint was tested only if the co-primary endpoint demonstrated statistical significance. The analyses were conducted in the Per Protocol Set (PPS), defined as the PMA P250016: FDA Summary of Safety and Effectiveness Data 10 of 33 {10} subset of all randomized participants without major protocol deviations, with the Intent-to-Treat Set (ITT), defined as all randomized subjects, serving as a supportive analysis set. . Secondary measures included assessments by both the investigator and the participant of the global aesthetic improvement at Week 8 using the Global Aesthetic Improvement Scale (GAIS), and the participants’ assessments at Week 8 using the Satisfaction with Lips module of the validated FACE-Q questionnaire. Additional effectiveness measures included the blinded evaluator’s assessments of participants’ average of treated lip fullness using MLFAS, and upper and lower lip fullness. Time course of participants’ satisfaction with lip treatment using the Satisfaction with Outcomes and Psychological Function modules of the FACE-Q. Participants’ self-perception of lip hydration and appearance using, as well as the par assessments of willingness to undergo treatment again. Responder rates at Week 8 using MLFAS as assessed by 3 blinded independent panel raters (IPR) using participant photographs were also evaluated as a secondary effectiveness endpoint. Secondary and additional endpoints were analyzed descriptively using summary statistics for continuous variables and frequency tables for categorical variables. The Merz Lips Fullness Assessment Scale (MLFAS) has been published in Journal of Drugs in Dermatology (JDD) – “doi:10.36849/JDD.7309 Citation: Bloom J, Kaplan J, Verma A, et al. Development and validation of a photonumeric scale for evaluation of lip fullness. J Drugs Dermatol. 2023;22(3):274-281. doi:10.36849/JDD.7309” <https://jddonline.com/articles/development-and-validation-of-a-photonumeric-scale-for-evaluation-of-lip-fullness-S1545961623P0274X/> ## **B. Accountability of Study Cohort** At the time of database lock, of 220 participants enrolled in the PMA study, 195 (88.6%) participants were available for analysis at the completion of the study (up to Week 64 for participants randomized to Belotero® Intense (+) Lidocaine participants and up to Week 52 for participants randomized to the comparator). A total of 250 participants were screened, and 220 participants were enrolled and randomized. Of these, 165 participants were randomized to Belotero® Intense (+) Lidocaine, and 55 participants were randomized to comparator. All randomized participants received the initial treatment, and 158/220 (71.8%) participants received a touch-up – 117/165 (70.9%) participants randomized to Belotero® Intense (+) Lidocaine and 41/55 (74.5%) participants randomized to the comparator. In addition, 116/165 (70.3%) Belotero® Intense (+) Lidocaine participants received retreatment. ---PMA P250016: FDA Summary of Safety and Effectiveness Data 11 of 33 {11} One-hundred ninety-five (195/220, 88.6%) participants completed the study: 149/165 (90.3%) Belotero® Intense (+) Lidocaine participants and 46/55 (83.6%) comparator participants. Of the 116 retreated participants, 113 (97.4%) completed the follow-up period after optional retreatment. Figure 1 provides an overview of the participant disposition for the pivotal study.  Figure 1: Participant Disposition The Safety Evaluation Set (SES) is the subset of all participants who were exposed to Belotero® Intense (+) Lidocaine or comparator device at least once. Participants in the SES analyses are analyzed as treated. The Intent-to-treat (ITT) includes all randomized participants. Participants in the ITT analyses are analyzed as randomized. The Per Protocol Set (PPS) is a subset of participants in the ITT without major protocol deviations. PMA P250016: FDA Summary of Safety and Effectiveness Data 12 of 33 {12} The analyses of the primary, co-primary and secondary effectiveness endpoints are based primarily on the PPS and additionally, for sensitivity purposes, on the ITT. All the remaining effectiveness endpoints are analyzed based on the PPS. ### C. Study Population Demographics and Baseline Parameters The demographics of the study population are typical for a pivotal dermal filler study for similar indications performed in the US. The majority of participants were female and White and identified themselves as Not Hispanic or Latino and White. In general, demographic data was comparable between Belotero® Intense (+) Lidocaine and comparator. Table 4 provides an overview of pivotal study demographics. **Table 4: Demographics** | Characteristic | | Belotero® Intense (+) Lidocaine (N=165) % (n/N) | Comparator (N = 55) % (n/N) | Total (N=220) % (n/N) | | --- | --- | --- | --- | --- | | **Sex** | Male | 2.4% (4/165) | 7.3% (4/55) | 3.6% (8/220) | | | Female | 97.6% (161/165) | 92.7% (51/55) | 96.4% (212/220) | | **Age (years)** | Mean (SD) | 46.5 (12.26) | 47.3 (10.26) | 46.7 (11.77) | | | Range (min, max) | (21-65) | (24-65) | (21-65) | | **Ethnicity** | Hispanic or Latino | 20.0% (33/165) | 25.5% (14/55) | 21.4% (47/220) | | | Not Hispanic or Latino | 80.0% (132/165) | 74.5% (41/55) | 78.6% (173/220) | | **Race** | White | 92.7% (153/165) | 90.9% (50/55) | 92.3% (203/220) | | | Black or African American | 3.6% (6/165) | 3.6% (2/55) | 3.6% (8/220) | | | Asian | 0.6% (1/165) | 1.8% (1/55) | 0.9% (2/220) | | | More than One Race | 3.0% (5/165) | 3.6% (2/55) | 3.2% (7/220) | | **Fitzpatrick Skin Type** | I | 3.6% (6/165) | 3.6% (2/55) | 3.6% (8/220) | | | II | 43.6% (72/165) | 40.0% (22/55) | 42.7% (94/220) | | | III | 30.3% (50/165) | 27.3% (15/55) | 29.5% (65/220) | | | IV | 13.3% (22/165) | 18.2% (10/55) | 14.5% (32/220) | | | V | 6.7% (11/165) | 10.9% (6/55) | 7.7% (17/220) | | | VI | 2.4% (4/165) | 0.0% (0/55) | 1.8% (4/220) | | Max = maximum, Min = minimum, n = number of observations, N = number of participants in the treatment group and analysis set, SD = standard deviation, Percentages based on N. | | | | | PMA P250016: FDA Summary of Safety and Effectiveness Data 13 of 33 {13} ## D. Safety and Effectiveness Results ### 1. Safety Results The analysis of safety was based on the Safety Evaluation Set (SES) of 220 participants available up to the final evaluation at Week 60. The key safety outcomes for this study are presented below in Table 5 through Table 10. Adverse effects are reported in Table 11. #### Adverse effects that occurred in the PMA clinical study: ##### • Common Treatment Responses (CTRs) Participants used electronic diary (“eDiary”) forms to record specific signs and symptoms experienced during the first 28 days after initial treatment, touch-up treatment (if performed), and repeat treatment (if performed). Participants were instructed to rate each common treatment response (CTR) listed on the diary as “Mild,” “Moderate,” “Severe,” or “None.” The severity and duration of CTRs reported by >5% of participants in either treatment group who completed post-treatment eDiaries after initial treatment, touch-up treatment (if performed), and repeat treatment (if performed) are summarized in Table 5 through Table 10. The majority of CTRs were mild or moderate in intensity and resolved within 15-28 days. The incidences, severity and duration of CTRs reported after the touch-up and repeat treatments with Belotero® Intense (+) Lidocaine were generally similar to the initial treatment. **Table 5: Common Treatment Site Responses by Maximum Severity After Initial Treatment Occurring in > 5% of Participants Treated for Lip Augmentation** | Common Treatment Response | Belotero® Intense (+) Lidocaine (N = 165 / M = 164) | | | | Comparator (N = 55 / M = 55) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | | Overall | 88.4% (165/164) | 24.4% (40/164) | 59.1% (97/164) | 4.9% (8/164) | 80.0% (44/55) | 23.6% (13/55) | 45.5% (25/55) | 10.9% (6/55) | | **Upper Lip** | | | | | | | | | | Swelling | 83.5% (137/164) | 37.2% (61/164) | 43.9% (72/164) | 2.4% (4/164) | 76.4% (42/55) | 30.9% (17/55) | 36.4% (20/55) | 9.1% (5/55) | | Lumps / Bumps | 72.6% (119/164) | 47.6% (78/164) | 24.4% (40/164) | 0.6% (1/164) | 56.4% (31/55) | 34.5% (19/55) | 20.0% (11/55) | 1.8% (1/55) | | Bruising | 72.0% (118/164) | 40.2% (66/164) | 29.3% (48/164) | 2.4% (4/164) | 49.1% (27/55) | 32.7% (18/55) | 14.5% (8/55) | 1.8% (1/55) | | Soreness | 70.1% (115/164) | 54.3% (89/164) | 15.2% (25/164) | 0.6% (1/164) | 61.8% (34/55) | 38.2% (21/55) | 21.8% (12/55) | 1.8% (1/55) | | Redness | 67.7% (111/164) | 52.4% (86/164) | 14.0% (23/164) | 1.2% (2/164) | 58.2% (32/55) | 41.8% (23/55) | 16.4% (9/55) | 0.0% (0/55) | | Pain / Tenderness | 67.1% (110/164) | 49.4% (81/164) | 16.5% (27/164) | 1.2% (2/164) | 61.8% (34/55) | 36.4% (20/55) | 23.6% (13/55) | 1.8% (1/55) | | Firmness / Hardness | 65.2% | 42.7% | 22.0% | 0.6% | 60.0% | 38.2% | 18.2% | 3.6% | PMA P250016: FDA Summary of Safety and Effectiveness Data 14 of 33 {14} | Common Treatment Response | Belotero^{®} Intense (+) Lidocaine (N = 165 / M = 164) | | | | Comparator (N = 55 / M = 55) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | | | (107/164) | (70/164) | (36/164) | (1/164) | (33/55) | (21/55) | (10/55) | (2/55) | | Discoloration | 28.7% (47/164) | 22.6% (37/164) | 5.5% (9/164) | 0.6% (1/164) | 18.2% (10/55) | 16.4% (9/55) | 1.8% (1/55) | 0.0% (0/55) | | Burning / Stinging | 23.8% (39/164) | 20.7% (34/164) | 3.0% (5/164) | 0.0% (0/164) | 27.3% (15/55) | 18.2% (10/55) | 9.1% (5/55) | 0.0% (0/55) | | Itching | 14.0% (23/164) | 14.0% (23/164) | 0.0% (0/164) | 0.0% (0/164) | 20.0% (11/55) | 16.4% (9/55) | 3.6% (2/55) | 0.0% (0/55) | | **Lower Lip** | | | | | | | | | | Swelling | 77.4% (127/164) | 37.8% (62/164) | 37.8% (62/164) | 1.8% (3/164) | 76.4% (42/55) | 38.2% (21/55) | 36.4% (20/55) | 1.8% (1/55) | | Lumps / Bumps | 70.1% (115/164) | 47.6% (78/164) | 21.3% (35/164) | 1.2% (2/164) | 58.2% (32/55) | 40.0% (22/55) | 18.2% (10/55) | 0.0% (0/55) | | Bruising | 67.7% (111/164) | 38.4% (63/164) | 26.8% (44/164) | 2.4% (4/164) | 56.4% (31/55) | 38.2% (21/55) | 18.2% (10/55) | 0.0% (0/55) | | Pain / Tenderness | 65.9% (108/164) | 50.0% (82/164) | 15.2% (25/164) | 0.6% (1/164) | 61.8% (34/55) | 34.5% (19/55) | 25.5% (14/55) | 1.8% (1/55) | | Firmness / Hardness | 65.2% (107/164) | 46.3% (76/164) | 18.3% (30/164) | 0.6% (1/164) | 58.2% (32/55) | 36.4% (20/55) | 20.0% (11/55) | 1.8% (1/55) | | Soreness | 61.6% (101/164) | 47.6% (78/164) | 13.4% (22/164) | 0.6% (1/164) | 63.6% (35/55) | 40.0% (22/55) | 21.8% (12/55) | 1.8% (1/55) | | Redness | 59.1% (97/164) | 44.5% (73/164) | 12.8% (21/164) | 1.8% (3/164) | 54.5% (30/55) | 32.7% (18/55) | 21.8% (12/55) | 0.0% (0/55) | | Discoloration | 29.9% (49/164) | 25.6% (42/164) | 3.7% (6/164) | 0.6% (1/164) | 20.0% (11/55) | 16.4% (9/55) | 3.6% (2/55) | 0.0% (0/55) | | Burning / Stinging | 22.0% (36/164) | 18.3% (30/164) | 3.7% (6/164) | 0.0% (0/164) | 34.5% (19/55) | 23.6% (13/55) | 10.9% (6/55) | 0.0% (0/55) | | Itching | 12.8% (21/164) | 12.8% (21/164) | 0.0% (0/164) | 0.0% (0/164) | 21.8% (12/55) | 18.2% (10/55) | 3.6% (2/55) | 0.0% (0/55) | M = number of participants in the corresponding treatment group with any diary data; N = Total number of participants in the corresponding treatment group. Percentages are based on M. **Table 6: Common Treatment Site Responses by Maximum Severity After Applicable Touch-up Occurring in > 5% of Participants Treated for Lip Augmentation** | Common Treatment Response | Belotero^{®} Intense (+) Lidocaine (N = 117 / M = 117) | | | | Comparator (N = 41 / M = 41) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | | Overall | 82.9% (97/117) | 39.3% (46/117) | 40.2% (47/117) | 3.4% (4/117) | 78.0% (32/41) | 17.1% (7/41) | 53.7% (22/41) | 7.3% (3/41) | | **Upper Lip** | | | | | | | | | | Swelling | 71.8% (84/117) | 47.9% (56/117) | 20.5% (24/117) | 3.4% (4/117) | 75.6% (31/41) | 29.3% (12/41) | 39.0% (16/41) | 7.3% (3/41) | | Lumps / Bumps | 57.3% (67/117) | 38.5% (45/117) | 18.8% (22/117) | 0.0% (0/117) | 58.5% (24/41) | 43.9% (18/41) | 14.6% (6/41) | 0.0% (0/41) | | Bruising | 57.3% (67/117) | 45.3% (53/117) | 12.0% (14/117) | 0.0% (0/117) | 46.3% (19/41) | 31.7% (13/41) | 14.6% (6/41) | 0.0% (0/41) | | Pain / Tenderness | 57.3% (67/117) | 47.0% (55/117) | 10.3% (12/117) | 0.0% (0/117) | 73.2% (30/41) | 56.1% (23/41) | 17.1% (7/41) | 0.0% (0/41) | PMA P250016: FDA Summary of Safety and Effectiveness Data 15 of 33 {15} | Common Treatment Response | Belotero® Intense (+) Lidocaine (N = 117 / M = 117) | | | | Comparator (N = 41 / M = 41) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | | **Firmness / Hardness** | 54.7% (64/117) | 41.9% (49/117) | 12.8% (15/117) | 0.0% (0/117) | 68.3% (28/41) | 48.8% (20/41) | 19.5% (8/41) | 0.0% (0/41) | | **Soreness** | 53.0% (62/117) | 42.7% (50/117) | 10.3% (12/117) | 0.0% (0/117) | 70.7% (29/41) | 56.1% (23/41) | 14.6% (6/41) | 0.0% (0/41) | | **Redness** | 43.6% (51/117) | 29.9% (35/117) | 13.7% (16/117) | 0.0% (0/117) | 58.5% (24/41) | 39.0% (16/41) | 19.5% (8/41) | 0.0% (0/41) | | **Discoloration** | 17.9% (21/117) | 17.1% (20/117) | 0.9% (1/117) | 0.0% (0/117) | 17.1% (7/41) | 12.2% (5/41) | 4.9% (2/41) | 0.0% (0/41) | | **Burning / Stinging** | 16.2% (19/117) | 11.1% (13/117) | 5.1% (6/117) | 0.0% (0/117) | 31.2% (13/41) | 29.3% (12/41) | 2.4% (1/41) | 0.0% (0/41) | | **Itching** | 7.7% (9/117) | 6.0% (7/117) | 1.7% (2/117) | 0.0% (0/117) | 12.2% (5/41) | 12.2% (5/41) | 0.0% (0/41) | 0.0% (0/41) | | **Lower Lip** | | | | | | | | | | **Firmness / Hardness** | 48.7% (57/117) | 35.9% (42/117) | 12.8% (15/117) | 0.0% (0/117) | 65.9% (27/41) | 39.0% (16/41) | 26.8% (11/41) | 0.0% (0/41) | | **Lumps / Bumps** | 47.9% (56/117) | 32.5% (38/117) | 15.4% (18/117) | 0.0% (0/117) | 48.8% (20/41) | 24.4% (10/41) | 24.4% (10/41) | 0.0% (0/41) | | **Pain / Tenderness** | 47.9% (56/117) | 38.5% (45/117) | 9.4% (11/117) | 0.0% (0/117) | 73.2% (30/41) | 56.1% (23/41) | 17.1% (7/41) | 0.0% (0/41) | | **Bruising** | 47.0% (55/117) | 35.0% (41/117) | 12.0% (14/117) | 0.0% (0/117) | 53.7% (22/41) | 29.3% (12/41) | 24.4% (10/41) | 0.0% (0/41) | | **Soreness** | 46.2% (54/117) | 36.8% (43/117) | 9.4% (11/117) | 0.0% (0/117) | 65.9% (27/41) | 43.9% (18/41) | 22.0% (9/41) | 0.0% (0/41) | | **Swelling** | 39.3% (71/117) | 39.3% (46/117) | 20.5% (24/117) | 0.9% (1/117) | 75.6% (31/41) | 34.1% (14/41) | 36.6% (15/41) | 4.9% (2/41) | | **Redness** | 39.3% (46/117) | 30.8% (36/117) | 8.5% (10/117) | 0.0% (0/117) | 53.7% (22/41) | 41.5% (17/41) | 12.2% (5/41) | 0.0% (0/41) | | **Discoloration** | 14.5% (17/117) | 12.8% (15/117) | 1.7% (2/117) | 0.0% (0/117) | 17.1% (7/41) | 14.6% (6/41) | 2.4% (1/41) | 0.0% (0/41) | | **Burning / Stinging** | 14.5% (17/117) | 12.0% (14/117) | 2.6% (3/117) | 0.0% (0/117) | 26.2% (11/41) | 22.0% (9/41) | 4.9% (2/41) | 0.0% (0/41) | | **Itching** | 4.3% (5/117) | 2.6% (3/117) | 1.7% (2/117) | 0.0% (0/117) | 9.8% (4/41) | 9.8% (4/41) | 0.0% (0/41) | 0.0% (0/41) | M = number of participants in the corresponding treatment group with any diary data; N = Total number of participants in the corresponding treatment group. Percentages are based on M. **Table 7: Common Treatment Site Responses by Maximum Severity After Optional Retreatment Occurring in > 5% of Participants Treated for Lip Augmentation** | Common Treatment Response | Belotero® Intense (+) Lidocaine (N = 116 / M = 114) | | | | | --- | --- | --- | --- | --- | | | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | | **Overall** | 71.9% (82/114) | 29.8% (34/114) | 38.6% (44/114) | 3.5% (4/114) | | **Upper Lip** | | | | | | **Swelling** | 67.5% (77/114) | 40.4% (46/114) | 36.3% (30/114) | 0.9% (1/114) | PMA P250016: FDA Summary of Safety and Effectiveness Data 16 of 33 {16} | Common Treatment Response | Belotero® Intense (+) Lidocaine (N = 116 / M = 114) | | | | | --- | --- | --- | --- | --- | | | Total % (n/M) | Mild % (n/M) | Moderate % (n/M) | Severe % (n/M) | | **Firmness / Hardness** | 60.5% (69/114) | 42.1% (48/114) | 17.5% (20/114) | 0.9% (1/114) | | **Pain / Tenderness** | 56.1% (64/114) | 44.7% (51/114) | 11.4% (13/114) | 0.0% (0/114) | | **Soreness** | 55.3% (63/114) | 45.6% (52/114) | 9.6% (11/114) | 0.0% (0/114) | | **Bruising** | 54.4% (62/114) | 30.7% (35/114) | 22.8% (26/114) | 0.9% (1/114) | | **Lumps / Bumps** | 54.4% (62/114) | 43.0% (49/114) | 11.4% (13/114) | 0.0% (0/114) | | **Redness** | 52.6% (60/114) | 37.7% (43/114) | 14.9% (17/114) | 0.0% (0/114) | | **Burning / Stinging** | 17.5% (20/114) | 13.2% (15/114) | 3.5% (4/114) | 0.9% (1/114) | | **Discoloration** | 15.8% (18/114) | 13.2% (15/114) | 2.6% (3/114) | 0.0% (0/114) | | **Itching** | 10.5% (12/114) | 8.8% (10/114) | 1.8% (2/114) | 0.0% (0/114) | | **Lower-Lip** | | | | | | **Swelling** | 60.5% (69/114) | 41.2% (47/114) | 18.4% (21/114) | 0.9% (1/114) | | **Firmness / Hardness** | 53.5% (61/114) | 41.2% (47/114) | 11.4% (13/114) | 0.9% (1/114) | | **Pain / Tenderness** | 50.9% (58/114) | 41.2% (47/114) | 9.6% (11/114) | 0.0% (0/114) | | **Soreness** | 50.9% (58/114) | 43.0% (49/114) | 7.9% (9/114) | 0.0% (0/114) | | **Bruising** | 50.0% (57/114) | 32.5% (37/114) | 17.5% (20/114) | 0.0% (0/114) | | **Lumps / Bumps** | 49.1% (56/114) | 36.8% (42/114) | 12.3% (14/114) | 0.0% (0/114) | | **Redness** | 43.0% (49/114) | 34.2% (39/114) | 8.8% (10/114) | 0.0% (0/114) | | **Burning / Stinging** | 18.4% (21/114) | 15.8% (18/114) | 2.6% (3/114) | 0.0% (0/114) | | **Discoloration** | 14.0% (16/114) | 10.5% (12/114) | 2.6% (3/114) | 0.9% (1/114) | | **Itching** | 6.1% (7/114) | 5.3% (6/114) | 0.9% (1/114) | 0.0% (0/114) | M = number of participants in the corresponding treatment group with any diary data; N = Total number of participants in the corresponding treatment group. Percentages are based on M. PMA P250016: FDA Summary of Safety and Effectiveness Data 17 of 33 {17} **Table 8: Common Treatment Site Responses by Maximum Duration After Initial Treatment Occurring in > 5% of Participants Treated for Lip Augmentation** | Common Treatment Response | Belotero® Intense (+) Lidocaine (N = 165 / M = 164) | | | | | Comparator (N = 55 / M = 55) | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Total % (n/M) | 1-3 Days % (n/M) | 4-7 Days % (n/M) | 8-14 Days % (n/M) | 15-28 Days % (n/M) | Total % (n/M) | 1-3 Days % (n/M) | 4-7 Days % (n/M) | 8-14 Days % (n/M) | 15-28 Days % (n/M) | | **Overall** | 88.4% (145/164) | 0.0% (0/164) | 1.8% (3/164) | 2.4% (4/164) | 84.1% (138/164) | 80.0% (44/55) | 0.0% (0/55) | 1.8% (1/55) | 0.0% (0/55) | 78.2% (43/55) | | **Upper Lip** | | | | | | | | | | | | **Swelling** | 83.5% (137/164) | 13.4% (22/164) | 28.0% (46/164) | 13.4% (22/164) | 28.7% (47/164) | 76.4% (42/55) | 14.5% (8/55) | 25.5% (14/55) | 1.8% (1/55) | 34.5% (19/55) | | **Lumps / Bumps** | 72.6% (119/164) | 9.1% (15/164) | 4.9% (8/164) | 5.5% (9/164) | 53.0% (87/164) | 56.4% (31/55) | 10.9% (6/55) | 9.1% (5/55) | 0.0% (0/55) | 36.4% (20/55) | | **Bruising** | 72.0% (118/164) | 6.7% (11/164) | 28.0% (46/164) | 20.1% (33/164) | 17.1% (28/164) | 49.1% (27/55) | 14.5% (8/55) | 16.4% (9/55) | 1.8% (1/55) | 16.4% (9/55) | | **Soreness** | 70.1% (115/164) | 23.2% (38/164) | 12.8% (21/164) | 15.2% (25/164) | 18.9% (31/164) | 61.8% (34/55) | 21.8% (12/55) | 18.2% (10/55) | 3.6% (2/55) | 18.2% (10/55) | | **Redness** | 67.7% (111/164) | 27.4% (45/164) | 16.5% (27/164) | 11.0% (18/164) | 12.8% (21/164) | 58.2% (32/55) | 20.0% (11/55) | 18.2% (10/55) | 1.8% (1/55) | 18.2% (10/55) | | **Pain / Tenderness** | 67.1% (110/164) | 15.2% (25/164) | 16.5% (27/164) | 12.8% (21/164) | 22.6% (37/164) | 61.8% (34/55) | 20.0% (11/55) | 18.2% (10/55) | 1.8% (1/55) | 21.8% (12/55) | | **Firmness / Hardness** | 65.2% (107/164) | 9.8% (16/164) | 11.6% (19/164) | 14.6% (24/164) | 29.3% (48/164) | 60.0% (33/55) | 18.2% (10/55) | 7.3% (4/55) | 7.3% (4/55) | 27.3% (15/55) | | **Discoloration** | 28.7% (47/164) | 11.0% (18/164) | 9.1% (15/164) | 3.0% (5/164) | 5.5% (9/164) | 18.2% (10/55) | 5.5% (3/55) | 5.5% (3/55) | 0.0% (0/55) | 7.3% (4/55) | | **Burning / Stinging** | 23.8% (39/164) | 15.2% (25/164) | 3.0% (5/164) | 1.8% (3/164) | 3.7% (6/164) | 27.3% (15/55) | 18.2% (10/55) | 1.8% (1/55) | 0.0% (0/55) | 7.3% (4/55) | | **Itching** | 14.0% (23/164) | 7.9% (13/164) | 1.8% (3/164) | 1.2% (2/164) | 3.0% (5/164) | 20.0% (11/55) | 5.5% (3/55) | 3.6% (2/55) | 0.0% (0/55) | 10.9% (6/55) | | **Lower Lip** | | | | | | | | | | | | **Swelling** | 77.4% (127/164) | 10.4% (17/164) | 26.2% (43/164) | 17.1% (28/164) | 23.8% (39/164) | 76.4% (42/55) | 20.0% (11/55) | 16.4% (9/55) | 3.6% (2/55) | 36.4% (20/55) | | **Lumps / Bumps** | 70.1% (115/164) | 11.6% (19/164) | 5.5% (9/164) | 5.5% (9/164) | 47.6% (78/164) | 58.2% (32/55) | 12.7% (7/55) | 5.5% (3/55) | 1.8% (1/55) | 38.2% (21/55) | | **Bruising** | 67.7% (111/164) | 10.4% (17/164) | 25.0% (41/164) | 16.5% (27/164) | 15.9% (26/164) | 56.4% (31/55) | 9.1% (5/55) | 18.2% (10/55) | 3.6% (2/55) | 25.5% (14/55) | | **Pain / Tenderness** | 65.9% (108/164) | 18.9% (31/164) | 14.6% (24/164) | 16.5% (27/164) | 15.9% (26/164) | 61.8% (34/55) | 12.7% (7/55) | 12.7% (7/55) | 9.1% (5/55) | 27.3% (15/55) | | **Firmness / Hardness** | 65.2% (107/164) | 16.5% (27/164) | 9.8% (16/164) | 15.2% (25/164) | 23.8% (39/164) | 58.2% (32/55) | 18.2% (10/55) | 5.5% (3/55) | 5.5% (3/55) | 29.1% (16/55) | | **Soreness** | 61.6% (101/164) | 16.5% (27/164) | 14.6% (24/164) | 17.1% (28/164) | 13.4% (22/164) | 63.6% (35/55) | 12.7% (7/55) | 16.4% (9/55) | 9.1% (5/55) | 25.5% (14/55) | | **Redness** | 59.1% (97/164) | 23.8% (39/164) | 13.4% (22/164) | 12.2% (20/164) | 9.8% (16/164) | 54.5% (30/55) | 16.4% (9/55) | 18.2% (10/55) | 1.8% (1/55) | 18.2% (10/55) | | **Discoloration** | 29.9% (49/164) | 15.9% (26/164) | 6.1% (10/164) | 4.9% (8/164) | 3.0% (5/164) | 20.0% (11/55) | 7.3% (4/55) | 5.5% (3/55) | 0.0% (0/55) | 7.3% (4/55) | | **Burning / Stinging** | 22.0% (36/164) | 14.0% (23/164) | 3.7% (6/164) | 1.8% (3/164) | 2.4% (4/164) | 34.5% (19/55) | 21.8% (12/55) | 7.3% (4/55) | 0.0% (0/55) | 5.5% (3/55) | | **Itching** | 12.8% (21/164) | 7.9% (13/164) | 1.2% (2/164) | 0.6% (1/164) | 3.0% (5/164) | 21.8% (12/55) | 10.9% (6/55) | 1.8% (1/55) | 0.0% (0/55) | 9.1% (5/55) | M = number of participants in the corresponding treatment group with any diary data; N = Total number of participants in the corresponding treatment group. Percentages are based on M. PMA P250016: FDA Summary of Safety and Effectiveness Data 18 of 33 {18} **Table 9: Common Treatment Site Responses by Maximum Duration After Applicable Touch-Up Occurring in > 5% of Participants Treated for Lip Augmentation** | Common Treatment Response | Belotero® Intense (+) Lidocaine (N = 117 / M = 117) | | | | | Comparator (N = 41 / M = 41) | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Total % (n/M) | 1-3 Days % (n/M) | 4-7 Days % (n/M) | 8-14 Days % (n/M) | 15-28 Days % (n/M) | Total % (n/M) | 1-3 Days % (n/M) | 4-7 Days % (n/M) | 8-14 Days % (n/M) | 15-28 Days % (n/M) | | **Overall** | 82.9% (97/117) | 0.0% (0/117) | 1.7% (2/117) | 3.4% (4/117) | 77.8% (91/117) | 78.5% (32/41) | 0.0% (0/41) | 2.4% (1/41) | 0.0% (0/41) | 75.6% (31/41) | | **Upper Lip** | | | | | | | | | | | | **Bruising** | 82.9% (97/117) | 14.5% (17/117) | 16.2% (19/117) | 11.1% (13/117) | 15.4% (18/117) | 46.3% (19/41) | 7.3% (3/41) | 7.3% (3/41) | 7.3% (3/41) | 24.4% (10/41) | | **Swelling** | 71.8% (84/117) | 17.1% (20/117) | 21.4% (25/117) | 8.5% (10/117) | 24.8% (29/117) | 75.6% (31/41) | 12.2% (5/41) | 19.5% (8/41) | 7.3% (3/41) | 36.6% (15/41) | | **Lumps / Bumps** | 57.3% (67/117) | 10.3% (12/117) | 6.0% (7/117) | 4.3% (5/117) | 36.8% (43/117) | 58.5% (24/41) | 17.1% (7/41) | 7.3% (3/41) | 2.4% (1/41) | 31.7% (13/41) | | **Pain / Tenderness** | 57.3% (67/117) | 17.9% (21/117) | 10.3% (12/117) | 8.5% (10/117) | 20.5% (24/117) | 73.2% (30/41) | 31.7% (13/41) | 7.3% (3/41) | 12.2% (5/41) | 22.0% (9/41) | | **Firmness / Hardness** | 54.7% (64/117) | 12.0% (14/117) | 11.1% (13/117) | 6.0% (7/117) | 25.6% (30/117) | 68.3% (28/41) | 22.2% (9/41) | 4.9% (2/41) | 4.9% (2/41) | 36.6% (15/41) | | **Soreness** | 53.0% (62/117) | 16.2% (19/117) | 6.8% (8/117) | 6.8% (8/117) | 23.1% (27/117) | 70.7% (29/41) | 34.1% (14/41) | 7.3% (3/41) | 4.9% (2/41) | 24.4% (10/41) | | **Redness** | 43.6% (51/117) | 19.7% (23/117) | 8.5% (10/117) | 6.0% (7/117) | 9.4% (11/117) | 58.5% (24/41) | 31.7% (13/41) | 4.9% (2/41) | 2.4% (1/41) | 19.5% (8/41) | | **Discoloration** | 17.9% (21/117) | 9.4% (11/117) | 2.6% (3/117) | 1.7% (2/117) | 4.3% (5/117) | 17.1% (7/41) | 4.9% (2/41) | 2.4% (1/41) | 0.0% (0/41) | 9.8% (4/41) | | **Burning / Stinging** | 16.2% (19/117) | 8.5% (10/117) | 0.9% (1/117) | 2.6% (3/117) | 4.3% (5/117) | 31.7% (13/41) | 24.4% (10/41) | 2.4% (1/41) | 0.0% (0/41) | 4.9% (2/41) | | **Itching** | 7.7% (9/117) | 3.4% (4/117) | 0.9% (1/117) | 0.9% (1/117) | 2.6% (3/117) | 12.2% (5/41) | 4.9% (2/41) | 2.4% (1/41) | 0.0% (0/41) | 4.9% (2/41) | | **Lower Lip** | | | | | | | | | | | | **Swelling** | 60.7% (71/117) | 12.8% (15/117) | 15.4% (18/117) | 14.5% (17/117) | 17.9% (21/117) | 75.6% (31/41) | 9.8% (4/41) | 24.4% (10/41) | 4.9% (2/41) | 36.6% (15/41) | | **Firmness / Hardness** | 49.6% (58/117) | 7.7% (9/117) | 6.8% (9/117) | 6.0% (7/117) | 28.2% (33/117) | 65.9% (27/41) | 17.1% (7/41) | 4.9% (2/41) | 2.4% (1/41) | 41.5% (17/41) | | **Lumps / Bumps** | 47.9% (56/117) | 6.0% (7/117) | 4.3% (5/117) | 6.0% (7/117) | 31.6% (37/117) | 48.8% (20/41) | 2.4% (1/41) | 7.3% (3/41) | 0.0% (0/41) | 39.0% (16/41) | | **Pain / Tenderness** | 47.9% (56/117) | 16.2% (19/117) | 12.0% (14/117) | 4.3% (5/117) | 15.4% (18/117) | 73.2% (30/41) | 26.8% (11/41) | 9.8% (4/41) | 9.8% (4/41) | 26.8% (11/41) | | **Bruising** | 47.0% (55/117) | 12.8% (15/117) | 8.5% (10/117) | 11.1% (13/117) | 14.5% (17/117) | 53.7% (22/41) | 14.6% (6/41) | 9.8% (4/41) | 4.9% (2/41) | 24.4% (10/41) | | **Soreness** | 46.2% (5/117) | 17.9% (21/117) | 6.8% (8/117) | 7.7% (9/117) | 13.7% (16/117) | 65.9% (27/41) | 22.0% (9/41) | 17.1% (7/41) | 2.4% (1/41) | 24.4% (10/41) | | **Redness** | 39.3% (46/117) | 13.7% (16/117) | 8.5% (10/117) | 4.3% (5/117) | 12.8% (15/117) | 53.7% (22/41) | 29.3% (12/41) | 7.3% (3/41) | 0.0% (0/41) | 17.1% (7/41) | | **Discoloration** | 14.5% (17/117) | 7.7% (9/117) | 2.6% (3/117) | 1.7% (2/117) | 2.6% (3/117) | 17.1% (7/41) | 4.9% (2/41) | 4.9% (2/41) | 0.0% (0/41) | 7.3% (3/41) | | **Burning / Stinging** | 14.5% (17/117) | 8.5% (10/117) | 1.7% (2/117) | 0.9% (1/117) | 3.4% (4/117) | 26.8% (11/41) | 22.0% (9/41) | 2.4% (1/41) | 0.0% (0/41) | 2.4% (1/41) | | **Itching** | 4.3% (5/117) | 1.7% (2/117) | 0.9% (1/117) | 0.0% (0/117) | 1.7% (2/117) | 9.8% (4/41) | 4.9% (2/41) | 2.4% (1/41) | 0.0% (0/41) | 2.4% (1/41) | M = number of participants in the corresponding treatment group with any diary data; N = Total number of participants in the corresponding treatment group. Percentages are based on M. PMA P250016: FDA Summary of Safety and Effectiveness Data 19 of 33 {19} **Table 10: Common Treatment Site Responses by Maximum Duration After Optional Retreatment Occurring in > 5% of Participants Treated for Lip Augmentation** | Common Treatment Response | Belotero® Intense (+) Lidocaine (N = 116 / M = 114) | | | | | | --- | --- | --- | --- | --- | --- | | | Total % (n/M) | 1-3 Days % (n/M) | 4-7 Days % (n/M) | 8-14 Days % (n/M) | 15-28 Days % (n/M) | | **Overall** | 71.9% (82/114) | 0.0% (0/114) | 0.0% (0/114) | 0.0% (0/114) | 71.9% (82/114) | | **Upper Lip** | | | | | | | **Swelling** | 67.5% (77/114) | 10.5% (12/114) | 20.2% (23/114) | 12.3% (14/114) | 24.6% (28/114) | | **Lumps / Bumps** | 54.4% (62/114) | 7.9% (9/114) | 6.1% (7/114) | 4.4% (5/114) | 36.0% (41/114) | | **Bruising** | 54.4% (62/114) | 7.0% (8/114) | 14.0% (16/114) | 13.2% (15/114) | 20.2% (23/114) | | **Soreness** | 55.3% (63/114) | 13.2% (15/114) | 13.2% (15/114) | 11.4% (13/114) | 17.5% (20/114) | | **Redness** | 52.6% (60/114) | 22.8% (26/114) | 11.4% (13/114) | 7.0% (8/114) | 11.4% (13/114) | | **Pain / Tenderness** | 56.1% (64/114) | 14.9% (17/114) | 13.2% (15/114) | 11.4% (13/114) | 16.7% (19/114) | | **Firmness / Hardness** | 60.5% (69/114) | 10.5% (12/114) | 7.0% (8/114) | 12.3% (14/114) | 30.7% (35/114) | | **Discoloration** | 15.8% (18/114) | 8.8% (10/114) | 0.9% (1/114) | 2.6% (3/114) | 3.5% (4/114) | | **Burning / Stinging** | 17.5% (20/114) | 9.6% (11/114) | 2.6% (3/114) | 2.6% (3/114) | 2.6% (3/114) | | **Itching** | 10.5% (12/114) | 5.3% (6/114) | 2.6% (3/114) | 0.9% (1/114) | 1.8% (2/114) | | **Lower Lip** | | | | | | | **Swelling** | 60.5% (69/114) | 12.3% (14/114) | 18.4% (21/114) | 12.3% (14/114) | 17.5% (20/114) | | **Lumps / Bumps** | 49.1% (56/114) | 12.3% (14/114) | 4.4% (5/114) | 7.0% (8/114) | 25.4% (29/114) | | **Bruising** | 50.0% (57/114) | 8.8% (10/114) | 20.2% (23/114) | 7.9% (9/114) | 13.2% (15/114) | | **Pain / Tenderness** | 50.9% (58/114) | 17.5% (20/114) | 7.9% (9/114) | 10.5% (12/114) | 14.9% (17/114) | | **Firmness / Hardness** | 53.5% (61/114) | 9.6% (11/114) | 8.8% (10/114) | 9.6% (11/114) | 25.4% (29/114) | | **Soreness** | 50.9% (58/114) | 14.9% (17/114) | 12.3% (14/114) | 9.6% (11/114) | 14.0% (16/114) | | **Redness** | 43.0% (49/114) | 17.5% (20/114) | 9.6% (11/114) | 6.1% (7/114) | 9.6% (11/114) | | **Discoloration** | 14.0% (16/114) | 5.3% (6/114) | 1.8% (2/114) | 3.5% (4/114) | 3.5% (4/114) | | **Burning / Stinging** | 18.4% (21/114) | 10.5% (12/114) | 1.8% (2/114) | 2.6% (3/114) | 3.5% (4/114) | | **Itching** | 6.1% (7/114) | 1.8% (2/114) | 2.6% (3/114) | 0.0% (0/114) | 1.8% (2/114) | M = number of participants in the corresponding treatment group with any diary data; N = Total number of participants in the corresponding treatment group. Percentages are based on M. PMA P250016: FDA Summary of Safety and Effectiveness Data 20 of 33 {20} # - • **Treatment-Related Treatment Emergent Adverse Events** Adverse Events (AEs) were also reported by the Treating Investigators at follow up visits. A treatment-emergent AE (TEAE) was defined as an AE that initially occurred or increased in severity on or after the treatment start date for the Belotero® Intense (+) Lidocaine or comparator group. An AE was considered to be related to the device or the injection procedure (i.e., “treatment-related”) if a causal relationship between the device or the injection procedure and the AE was at least reasonably possible. CTRs that lasted beyond 28 days were considered AEs. After initial treatment (or touch-up treatment if performed), a total of 73 treatment-related TEAEs were reported in 17.0% (28/165) of participants treated with Belotero® Intense (+) Lidocaine. Thirty (30) treatment-related TEAEs were reported in 14.5% (8/55) of participants treated with the comparator product. After repeat treatment in the Belotero® Intense (+) Lidocaine group, a total of 38 treatment-related TEAEs were reported in 11.2% (13/116) of participants. Related TEAEs occurring in > 5% of treated participants in either treatment group are summarized in Table 11. Overall, related TEAEs were typically mild in intensity and all resolved without sequelae. There were no serious treatment-related adverse events reported. **Table 11: Treatment-Related TEAE > 5% of Treated Participants for Lip Augmentation by Adverse Event Preferred Term** | Adverse Event | Belotero® Intense (+) Lidocaine Initial Treatment (N=165) | | Comparator Initial Treatment (N=55) | | Belotero® Intense (+) Lidocaine Repeat Treatment (N=116) | | | --- | --- | --- | --- | --- | --- | --- | | | Participants % (n/N) | Number of Events | Participants % (n/N) | Number of Events | Participants % (n/N) | Number of Events | | **Overall** | 17.0% (28/165) | 73 | 14.5% (8/55) | 30 | 11.2% (13/116) | 38 | | **Injection site mass** | 14.5% (24/165) | 44 | 10.9% (6/55) | 14 | 8.6% (10/116) | 15 | | **Injection site induration** | 4.2% (7/165) | 12 | 7.3% (4/55) | 7 | 4.3% (5/116) | 9 | | N = number of participants in the treatment group and analysis set, n = number of participants in respective subset, Percentages are based on N. A participant with more than one treatment-related TEAE within an Adverse Event was counted once. | | | | | | | Common treatment-related TEAEs included injection site mass, induration and swelling. Other related TEAEs reported by ≤ 5% of participants after initial (or touch-up treatment) Belotero® Intense (+) Lidocaine treatment included (in order of number of participants who experienced the event): injection site swelling, pain, discoloration, bruising, erythema, edema, and oral herpes. After repeat treatment, treatment-related TEAEs occurring in ≤ 5% of participants included (in order of number of participants who experienced the event): injection site pain, swelling, bruising, discoloration, and erythema. Related TEAEs generally resolved in an average of 43.5 days for participants treated with Belotero® Intense (+) Lidocaine and in an average of 50.6 days for participants treated with the comparator group. All treatment-related TEAEs were resolved by the end of the study. PMA P250016: FDA Summary of Safety and Effectiveness Data 21 of 33 {21} - **Safety Subgroup Analyses** Subgroup analyses were completed to analyze treatment-related AEs by Fitzpatrick Skin Phototype, age, gender, race and ethnicity. No increased safety risks were observed for any specific groups. - **Treatment-Related Delayed-Onset TEAEs** In the clinical study, 4 participants experienced treatment related TEAEs > 21 days after Belotero® Intense (+) Lidocaine initial treatment or touch-up treatment. These delayed onset reactions included: injection site bumps (mass) (1.8%, 3/165 participants); induration (0.6%, 1/165 participants); edema (0.6%, 1/165 participants); and pain (0.6%, 1/165 participants). Five participants experienced delayed-onset treatment-related TEAEs after repeat treatment with Belotero® Intense (+) Lidocaine, including: injection site bumps (mass) (3.4%, 4/165 participants); induration (1.7%, 2/165 participants); pain (1.7%, 2/165 participants); discoloration (0.9%, 1/165 participants); and erythema (0.9%, 1/165 participants). Delayed-onset TEAEs were mild in intensity and resolved without sequelae. Generally, the time to onset ranged from 23 to 29 days after the last treatment (initial, touch-up or repeat), with only one case of edema with a time of onset of 102 days. This case was mild and resolved within 17 days. - **Other Safety Assessments** Vision safety assessments were performed at the screening visit and throughout the study. All abnormal visual acuity results were evaluated by the investigator and determined to be non-serious, and not related to treatment with either Belotero® Intense (+) Lidocaine or the comparator. Lip safety assessments such as functional features of the lips, lip sensitivity and sensation, lip symmetry, and movement were evaluated at the screening visit and throughout the study. None of the lip assessments were remarkable or presented any safety concerns after treatment with either Belotero® Intense (+) Lidocaine or the comparator. Treating investigators conducted a neurological exam 30 minutes after each treatment visit. No abnormal neurological results were reported during the study. PMA P250016: FDA Summary of Safety and Effectiveness Data 22 of 33 {22} ## 2. Effectiveness Results: The analysis of effectiveness was based on 158 evaluable participants (PPS) and 162 evaluable participants (ITT, Observed Cases) at the primary endpoint visit at Week 8. Comparator group had 52 evaluable participants (PPS and ITT Observed Cases) at the Week 8 time point. Key effectiveness outcomes are presented in Table 12 and Table 13. The co-primary and primary effectiveness endpoints were met. MLFAS responder rate of participants treated with Belotero® Intense (+) Lidocaine at Week 8 post-last treatment demonstrated a treatment effect statistically significantly greater than the prespecified performance goal of 50%, as the lower limit of the two-sided 95% confidence interval exceeded the target margin of 50%. In the PPS, 91.1% (144/158) of participants treated with Belotero® Intense (+) Lidocaine and 90.4% (47/52) of participants treated with the comparator showed a ≥ 1-point improvement in overall lip fullness, with an observed mean change from baseline to Week 8 post-last treatment on the MLFAS of 1.3 for participants treated with Belotero® Intense (+) Lidocaine and 1.2 for participants treated with comparator. The study met the goal of demonstrating noninferiority of Belotero® Intense (+) Lidocaine compared to comparator, as the lower bound of the two-sided 95% confidence interval for difference between groups was > -0.5 point. The analysis results based on observed cases in the ITT population are consistent with the primary analysis result based on the PPS. **Table 12: Co-primary: Responder Rate in MLFAS at Week 8 Post-Last Treatment as Assessed by the Blinded Evaluator** | | PPS | ITT (Observed Cases) | | --- | --- | --- | | | Belotero® Intense (+) Lidocaine (N=158) | Belotero® Intense (+) Lidocaine (N=162) | | Responder rate, n/N (%) | 144/158 (91.1%) | 148/162 (91.4%) | | Two-sided 95% CI* | (85.6, 95.1) | (85.9, 95.2) | *Derived from 95% Clopper-Pearson exact confidence interval. **Table 13: Primary: Change from Baseline to Week 8 Post-Last Treatment in MLFAS as Assessed by the Blinded Evaluator** | | PPS | | ITT (Observed Cases) | | | --- | --- | --- | --- | --- | | | Belotero® Intense (+) Lidocaine (N=158) | Comparator (N=52) | Belotero® Intense (+) Lidocaine (N=162) | Comparator (N=52) | | Observed means | 1.31 | 1.23 | 1.31 | 1.23 | | Between group difference, 95% CI* | 0.1 (0.0, 0.3) | | 0.1 (0.0, 0.3) | | PMA P250016: FDA Summary of Safety and Effectiveness Data 23 of 33 {23} *A baseline adjusted analysis of covariance (ANCOVA) with baseline value, fixed effects treatment, site, and Fitzpatrick skin type groups (I – III & IV – VI) is used to derive a two-sided 95% confidence interval. Throughout the follow-up period, Belotero® Intense (+) Lidocaine continued to provide a clinically significant improvement in lip fullness, with the majority of participants demonstrating improvement up to 48 weeks after treatment. The proportion MLFAS responders (≥ 1 point mean change on MLFAS as assessed by blinded evaluator) by time point is presented in Table 14. Up to Week 48 in the Belotero® Intense (+) Lidocaine group, improvements in upper and lower lip fullness were similar to the improvements observed in overall lip fullness. **Table 14: Effectiveness Results through Week 48 (PPS) By Blinded Evaluator** | | Belotero® Intense (+) Lidocaine % (n/N) | Comparator % (n/N) | | --- | --- | --- | | Week 4 | 84.2% (133/158) | 67.3% (35/52 ) | | Week 8 | 91.1% (144/158) | 90.4% (47/52) | | Week 16 | 89.6% (138/154) | 78.4% (40/51) | | Week 24 | 78.8% (119/151) | 72.9% (35/48) | | Week 36 | 69.8% (104/149) | 63.8% (30/47) | | Week 48 | 48.7% (73/150) | 47.8% (22/46) | When evaluated by IPR, 92/158 (58.2%) participants randomized to Belotero® Intense (+) Lidocaine participants and 31/52 (59.6%) randomized to the comparator participants showed a treatment response at Week 8 post-last treatment, according to MLFAS. According to the GAIS, at Week 8, all (100%) participants treated with Belotero® Intense (+) Lidocaine showed some level of aesthetic improvement when assessed by the investigator, with 92.4% (146/158) scoring ‘much improved’ or ‘very much improved’ in appearance. By Week 48, 92% (138/150) of treated participants continued to show some level of aesthetic improvement (i.e., ‘improved’, ‘much improved’, or ‘very much improved’). Similarly, at Week 8, all (100%) participants treated with Belotero® Intense (+) Lidocaine reported some level of aesthetic improvement according to the GAIS, with 91.1% (144/158) of treated participants scoring themselves as ‘much improved’ or ‘very much improved’ in appearance. By Week 48, 90% (135/150) of treated participants continued to report some level of aesthetic improvement (i.e., ‘improved’, ‘much improved’, or ‘very much improved’). At Week 8, participants treated with Belotero® Intense (+) Lidocaine reported improvement in satisfaction with their lips, based on the *Satisfaction with Lips* module of the FACE Q PMA P250016: FDA Summary of Safety and Effectiveness Data 24 of 33 {24} questionnaire. The mean score increased from 37.9 at baseline to 88.7 eight weeks post-last treatment, corroborating the GAIS findings that indicate participants were satisfied with the appearance of their lips. Similarly, participants reported being satisfied with the outcome of Belotero® Intense (+) Lidocaine treatment up to 48 weeks, based on the *Satisfaction with Outcomes* module of the FACE Q questionnaire. Participants treated with Belotero® Intense (+) Lidocaine also self-reported improvements on the FACE-Q *Psychological Function* module, with an increase of mean scores from 72.9 at baseline to 88.5 at Week 8 post-last treatment. These improvements were maintained to Week 48 post-last treatment, with participants self-reporting a mean score of 84.9. This validated quality-of-life scale asks respondents to answer 10 questions with their facial appearance in mind measuring concepts such as feeling happy, positive, confidence, self-acceptance, etc. which evaluated how confident, attractive or happy the participants felt after treatment. According to responses to the lip hydration and appearance questionnaire, improvements were maintained through Week 48 in the Belotero® Intense (+) Lidocaine treatment group, with mean scores increasing from 14.3 at baseline to 26.0 at Week 8, 26.1 at week 16 and reaching 23.3 at Week 48 post last treatment. The majority (92.4%, 133/144) of participants treated with Belotero® Intense (+) Lidocaine were satisfied with treatment and most (66.7%) reported being extremely likely to receive future treatment. No differences in overall lip volume responder rates at week 8 were observed based on the following subgroup analyses: baseline lip fullness, sex, race, ethnicity, investigational site, and Fitzpatrick Skin Phototype. The results of these subgroup analyses were consistent with the co-primary and the primary endpoint analyses in the overall population. ### **Follow-Up After Repeat Treatment** At Week 48, repeat treatment with Belotero® Intense (+) Lidocaine was administered to 116 participants. In the subgroup for retreated participants, 79.1% of retreated participants with evaluable data showed at least a 1-point improvement in treated lip fullness, based on the blinded evaluator assessment at 12 weeks after repeat treatment, i.e. at week 60 after initial treatment or touch-up, if applicable. In the subgroup for not retreated participants, 60 weeks post last Belotero® Intense (+) Lidocaine treatment, 45.7% of participants with evaluable data showed at least a 1-point improvement in treated lip fullness, based on the blinded evaluator assessment. GAIS improvement, as determined by the investigator and the participant, remained after repeat treatment, with investigators rating 96.6% of participants with any improvement and 95.2% of participants self-reporting any improvement 12 weeks after repeat treatment, or 60 weeks post-last treatment (i.e., without repeat treatment). These findings further demonstrate that treatment with Belotero® Intense (+) Lidocaine resulted in overall aesthetic improvement of the lips. ---PMA P250016: FDA Summary of Safety and Effectiveness Data 25 of 33 {25} ### 3. Subgroup Analyses The following baseline characteristics were evaluated for potential association with safety and effectiveness outcomes: The study was not specifically powered for sex, age, race or ethnicity. No clinically significant tolerability concerns were observed when stratifying related TEAEs by sex, age group, FST categories, race, or ethnicity. #### Safety Analysis: **FST:** Overall rates for related TEAEs were higher among participants with FST I to III (21.0% participants) compared to IV to VI (13.2% participants). This effect was observed in both treatment groups: Belotero® Intense (+) Lidocaine (FST I to III: 21.9%; FST IV to VI 16.2%) and comparator (FST I to III: 17.9%; FST IV to VI: 6.3%) but was more pronounced in the comparator group. Only 16 participants with FST IV to VI were treated with comparator. Due to the low sample size in this subgroup, the results of the comparator subgroup with FST IV to VI should be interpreted with caution. The most frequently reported related TEAEs were injection-site mass (I to III: 27/167 participants, 16.2%; IV to VI: 6/53 participants, 11.3%) followed by injection-site induration (I to III: 14/167 participants, 8.4%; IV to VI: 2/53 participants, 3.8%). **Race:** In terms of race, participants were analyzed separately as White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, and more than one race. Overall, the proportion of participants with at least one treatment-related TEAE was 20.2% in participants with White race and 50.0% in participants with Asian race. There were no treatment-related TEAEs in participants with Black or African American race, American Indian or Alaska Native race, Native Hawaiian or Other Pacific Islander race or more than one race. A similar pattern was observed in the Belotero® Intense (+) Lidocaine group, with treatment-related TEAEs reported in 21.6% of White participants and in the single Asian participant enrolled (100.0%). **Age:** In terms of age, safety data were grouped into participants of 21-30 years, 31-40 years, 41-50 years and 51-65 years. Treatment-related TEAE rates were generally similar among participants aged 21-30 years (17.2%), 41-50 years (18.3%), and 51-65 years (15.8%) but were higher in participants aged 31-40 years (30.6%). A similar pattern was observed in the Belotero® Intense (+) Lidocaine group, where treatment-related TEAEs occurred in 16.0%, 17.1%, and 16.4% of participants aged 21-30, 41-50, and 51-65 years, respectively, compared with 42.3% of participants aged 31-40 years. **Sex:** In terms of sex, treatment-related TEAEs were analyzed in female and male participants separately. Overall, female participants experienced at least one treatment-related TEAE (19.8%), and there was no treatment-related TEAEs for male participants. **Ethnicity:** In terms of ethnicity, treatment-related TEAEs were analyzed for Hispanic or Latino vs. Not Hispanic or Latino. Overall, treatment-related TEAEs were less frequent in Hispanic or Latino participants (14.9%) than in Not Hispanic or Latino participants (20.2%). A similar trend was observed in the Belotero® Intense (+) Lidocaine group, with treatment-related TEAEs reported in ---PMA P250016: FDA Summary of Safety and Effectiveness Data 26 of 33 {26} 15.2% of Hispanic or Latino participants compared with 22.0% of Not Hispanic or Latino participants. # **Effectiveness Analysis:** All subgroup analysis are based on the MLFAS assessments by the blinded evaluators at Week 8 post last treatment. Responders were categorized as participants with ≥ 1-point MLFAS improvement compared to baseline on treated lip(s). If both lips were treated, the participant was categorized as a responder only if MLFAS improvement was attained on both lips. FST: FST effectiveness data were stratified by FST I-III (lower FST) and IV-VI (higher FST). 91.1% (112/123) of Belotero® Intense (+) Lidocaine treated participants with FST I-III were assessed as responders at Week 8 post last treatment. Results for FST I-III participants randomized to the comparator device showed comparable results of 89.2% (33/37). Responder rates were slightly higher for participants with FST IV-VI independently if treated with Belotero® Intense (+) Lidocaine (91.4%; 32/35) or the comparator (93.3%, 14/15). Race: 91.1% (133/146) of White participants treated with Belotero® Intense (+) Lidocaine were assessed as responders at Week 8 post last treatment, similarly 89.4% (42/47) participants treated with the comparator were assessed as responders. Black or African American participants treated with Belotero® Intense (+) Lidocaine showed responder rates of 83.3% (5/6) vs. all comparator treated participants (100%; 2/2) were assessed as responders. Due to the small comparator subgroup (n=2), the result is not representative. Similar limitations apply to Asian or More than One Race categories. Age: For age effectiveness data were stratified by four age groups of participants of 21-30 years, 31-40 years, 41-50 years, and 51-65 years, respectively. For Belotero® Intense (+) Lidocaine treated participants the responder rates in the two younger age groups was minimally higher compared to the two older age groups: 21-30 years = 95.7% (22/23), 31-40 years = 96.0% (24/25), 41-50 years = 89.5% (34/38) and 51-65 years = 88.9% (64/72). Participants treated with the comparator device showed similar results for the higher age groups 41-50 years = 94.1% (16/17) and 51-65 years = 90.9% (20/22). Results in the younger age groups 21-30 years = 100% (4/4), 31-40 years = 77.8% (7/9) should be interpreted cautiously due to the small sample size. Sex: Responder rates at Week 8 post last treatment showed 100% for male participants treated with Belotero® Intense (+) Lidocaine (4/4) and with the comparator (3/3). For female participants the responder rate at Week 8 was 90.9% (140/154) for those treated with Belotero® Intense (+) and 89.8% (44/49) for those treated with the comparator. Given the small sample size of the male cohort, the results should be interpreted cautiously and should not be overinterpreted. Ethnicity: Effectiveness data assessed at Week 8 post last treatment between Hispanic or Latino and Not Hispanic or Latino participants did not show clinically relevant differences between both groups PMA P250016: FDA Summary of Safety and Effectiveness Data 27 of 33 {27} as well as the treatment groups. Belotero® Intense (+) Lidocaine treated participants with Hispanic or Latino ethnicity showed a responder rate of 90.3% (28/31) while participants with Non-Hispanic or Latino ethnicity reported 91.3% (116/127). Data for the comparator device are comparable with 92.3% (12/13) for participants with Hispanic or Latino ethnicity and 89.7% (35/39) for participants with Non-Hispanic or Latino ethnic background. Overall, the subgroup effectiveness analyses did not reveal any population in which Belotero® Intense (+) Lidocaine appeared to perform less effectively than expected. Treatment effects were generally consistent across demographic and baseline characteristic subgroups, with responder rates remaining high and comparable to those observed in the overall study population. The results support the consistency and robustness of the effectiveness findings across the evaluated subgroups, while recognizing the limitations associated with small sample sizes in certain categories. The results of these subgroup analyses were consistent with the co-primary and the primary effectiveness endpoint analyses in the overall population. #### **4. Pediatric Extrapolation:** In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population. ### **XI. Financial Disclosure** The Financial Disclosure by Clinical Investigators regulation (21 CFR Part 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included fourteen investigators. Thirteen of the fourteen investigators have, by way of a signed financial disclosure/certification form, verified that they had no applicable financial arrangements with Merz North America Inc. as defined in 21 CFR Part 54. One of the fourteen investigators had financial arrangements with the sponsor to be disclosed under 21 CFR 54.2 (b), not affecting the outcome of the pivotal clinical study. The nature of these disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) is described below: - Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: none - Significant payment of other sorts: one - Proprietary interest in the product tested held by the investigator: none - Significant equity interest held by investigator in sponsor of covered study: none PMA P250016: FDA Summary of Safety and Effectiveness Data 28 of 33 {28} The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. The information provided does not raise any questions about the reliability of the data. ## XII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the General and Plastic Surgery Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel. ## XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES ### A. Effectiveness Conclusions Belotero Intense® (+) Lidocaine met the pre-specified primary endpoint, and the secondary endpoints to support product effectiveness. The responder rate of Belotero® Intense (+) Lidocaine, demonstrated a statistically significant treatment effect as the lower limit of the 95% CI exceeded the 50% margin (95% CI: [85.6, 95.1]) in PPS. Results of supportive analysis in the Intent-to-Treat Set based on worst-case imputation were consistent with primary analysis. Non-inferiority of Belotero® Intense (+) Lidocaine compared with an approved HA dermal filler was demonstrated. In the PPS, the lower bound of the ANCOVA-based 95% confidence interval for the difference in least squares (LS) mean change from baseline to Week 8 (post-treatment or touch-up) (Belotero® Intense (+) Lidocaine minus comparator) was 0.0, exceeding the non-inferiority margin of -0.5 (95% CI: [0.0, 0.3]). This finding was consistent with the supportive analysis in the Intent-to-Treat Set based on observed cases. The data confirms that Belotero Intense® (+) Lidocaine is effective for submucosal and/or subcutaneous implantation for lip augmentation in adults over the age of 21. See data above. Subgroup analyses were performed on gender, Fitzpatrick Skin Type, age, etc. Treatment group participants showed consistent responder rates across the different subgroups. ### B. Safety Conclusions The risks of the device are based on nonclinical laboratory and animal studies, as well as data collected in a clinical study conducted to support PMA approval as described above. No device-related serious adverse events were reported. Overall, a total of 141 related non-serious adverse events were reported in 42/220 (19.1%) participants – 34/165 (20.6%) in Belotero® Intense (+) Lidocaine participants and 8/55 (14.5%) in comparator participants, with ---PMA P250016: FDA Summary of Safety and Effectiveness Data 29 of 33 {29} 111 and 30 related AEs, respectively. Overall, related AEs were typically mild (39/220 participants, 17.7%) and all events resolved without sequelae (42/220 participants, 19.1%). Three Belotero® Intense (+) Lidocaine (1.8%) participants experienced a related AE of moderate intensi…