RHA® Redensity Mepi, RHA®2 Mepi, RHA®3 Mepi, RHA®4 Mepi

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION Device Generic Name: Injectable Dermal Filler Device Trade Name: RHA® Redensity™ Mepi RHA® 2 Mepi RHA® 3 Mepi RHA® 4 Mepi Device Product code: LMH (Implant, Dermal, For Aesthetic Use) Applicant's Name and Address: TEOXANE SA Les Charmilles Rue de Lyon, 105 CH - 1203 Geneva, Switzerland Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P170002/S026 Date of FDA Notice of Approval: October 13, 2023 The original PMA for RHA®2, RHA®3 and RHA®4 (P170002) was approved on October 19, 2017. RHA®2, RHA®3 and RHA®4 are indicated for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLFs), in adults aged 22 years or older. The SSED to support the NLF indication for RHA®2, RHA®3 and RHA®4 is available on the CDRH website and is incorporated by reference here. RHA® Redensity™ was approved under supplement P170002/S012 on December 22, 2021 for injection into the dermis and superficial dermis of the face, for the correction of moderate to severe dynamic perioral rhytids, in adults aged 22 years or older. The SSED to support the perioral rhytids indication for RHA® Redensity™ is available on the CDRH website and is incorporated by reference here. RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi are being submitted as a panel-track supplement (P170002/S026) to the RHA® Redensity™, RHA®2, RHA®3, and RHA®4 PMA (P170002) to request changes in the design or performance of the device. The current supplement was submitted for RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi, and RHA®4 Mepi to modify the device formulation by using 0.3% w/w of mepivacaine instead of 0.3% w/w of lidocaine for pain reduction. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 1 {1} ## **II. INDICATIONS FOR USE** RHA® Redensity™ Mepi is indicated for injection into the dermis and superficial dermis of the face for the correction of moderate to severe dynamic perioral rhytids, in adults aged 22 years or older. RHA®2 Mepi is indicated for injection into the mid-to-deep dermis for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older. RHA®3 Mepi is indicated for injection into the mid-to-deep dermis for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older. RHA®4 Mepi is indicated for injection into the deep dermis to superficial subcutaneous tissue for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF), in adults aged 22 years or older. ## **III. CONTRAINDICATIONS** - RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi are contraindicated for patients with severe allergies manifested by a history of anaphylaxis or history or presence of multiple severe allergies. - RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi contain trace amounts of gram positive bacterial proteins, and is contraindicated for patients with a history of allergies to such material. - RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi should not be used in patients with previous hypersensitivity to local anesthetics of the amide type, such as lidocaine and mepivacaine. - RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi should not be used in patients with bleeding disorders. ## **IV. WARNINGS AND PRECAUTIONS** The warnings and precautions can be found in RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi labeling. ## **V. DEVICE DESCRIPTION** RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi are viscoelastic, sterile, non-pyrogenic, clear, colorless, and biodegradable gel implants of both crosslinked and non- PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 2 {2} crosslinked hyaluronic acid. They are produced with sodium Hyaluronic Acid (NaHA) with a concentration of 15 mg/g (RHA® Redensity™ Mepi) and 23 mg/g (RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi) obtained from bacterial fermentation using a Streptococcus equi bacterial strain, crosslinked with 1,4-butanediol diglycidyl ether (BDDE) and reconstituted in a physiological buffer (pH 7.3). The devices exist in four formulations, from the least to the most crosslinked: - RHA® Redensity™ (least cross-linked) - RHA®2 Mepi - RHA®3 Mepi - RHA®4 Mepi (most cross-linked) RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi contain 0.3% mepivacaine hydrochloride to reduce pain on injection. Syringes contain 1 ml of RHA® Redensity™ Mepi, RHA®2 Mepi, or RHA®3 Mepi. Syringes contain 1.2 mL of RHA®4 Mepi. RHA® Redensity™ Mepi and RHA®2 Mepi are supplied with two 30G ½ inch hypodermic needles. RHA®3 Mepi, and RHA®4 Mepi are supplied with two 27G ½ inch hypodermic needles. ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction of moderate to severe dynamic perioral rhytids or for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLF). Alternatives in the treatment of facial wrinkles and folds and perioral rhytids include invasive surgery (face-lift, rhytidectomy, etc.). Less invasive alternatives include injection of other hyaluronic acid dermal fillers or autologous fat transfer. Each alternative has its own benefits and risks when considering for example, the duration of the treatment, the cost of the treatment, the downtime associated with the treatment, the aesthetic effectiveness of the treatment, the type and duration of the adverse events associated with treatment. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi are only available in the United States. There is no marketing history for these products. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 3 {3} ## **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH** Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. Common treatment responses which can occur with the use of RHA$^{®}$ Redensity$^{™}$ Mepi, RHA$^{®}$2 Mepi, RHA$^{®}$3 Mepi, RHA$^{®}$4 Mepi and other dermal fillers, include (in alphabetical order): bruising, discoloration, firmness (induration), itching, lumps/bumps (injection site mass), pain, redness, swelling and tenderness. All these common treatment responses were seen in the clinical studies. Rare but serious adverse events associated with the intravascular injection of soft tissue fillers in the face have been reported and include temporary or permanent vision impairment or blindness, cerebral ischemia or cerebral hemorrhage leading to stroke, skin necrosis, and damage to underlying facial structures. RHA$^{®}$ Redensity$^{™}$ Mepi, RHA$^{®}$2 Mepi, RHA$^{®}$3 Mepi, RHA$^{®}$4 Mepi are the exact same products as RHA$^{®}$ Redensity$^{™}$, RHA$^{®}$2, RHA$^{®}$3, RHA$^{®}$4 respectively except that the RHA$^{®}$ Mepi family of products contains 0.3% of the anesthetic mepivacaine while the RHA$^{®}$ family of product contains 0.3% of the anesthetic lidocaine. Both anesthetics agents are of the same family with the same mechanisms effects. Both have an effect limited in time and are released from the gel within 24 hours. Therefore, post-marketing surveillance data of the RHA$^{®}$ family of products containing lidocaine are applicable to the RHA$^{®}$ Mepi family of products. The RHA$^{®}$ Mepi family of product has not been commercialized yet but the RHA$^{®}$ family of products has been commercialized since 2015 outside the United States and since 2020 in the United States. The following adverse events have been reported for RHA$^{®}$ family of products as part of the post-marketing surveillance outside the United States. These treatment reactions occurred when RHA$^{®}$ products were used for a wide range of indications, including but not limited to perioral rhytids or nasolabial folds. The following adverse events were reported with a prevalence equal or superior to 1 occurrence for 100,000 syringes: skin edema, injection site masses (lumps and bumps), skin swelling, skin induration, vascular skin disorder (such as vessel compression/occlusion), pain, ecchymosis, erythema, skin discoloration, skin infection and inflammatory reaction. Additionally, other less frequent adverse reactions have also been reported, and include dermal filler overcorrection, allergic reaction, product misplacement, fibrosis, skin necrosis, papules, granuloma, injection site movement impairment, paraesthesia, urticaria and device migration. In many cases the symptoms resolved without any treatment. Reported treatments and procedures included the use of (in alphabetical order): analgesics, antibiotics, anti-histamines, anti-inflammatories, anti-viral, implant dissolution (hyaluronidase), drainage, excision, incision, massage, and vasodilators. For the specific adverse events that occurred in the clinical study, please see Section X below. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 4 {4} ## **IX. SUMMARY OF NONCLINICAL STUDIES** RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi were extensively tested and characterized through physical and chemical testing (Table 1), and biocompatibility studies (Table 2). Preclinical testing results were adequate to support the initiation of a human clinical study of the dermal filler and to support a PMA. ### **A. Laboratory Studies** **Table 1: Physical and Chemical Testing – Requirements for RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi** | Test | Purpose | Results | | --- | --- | --- | | NaHA content | To confirm the NaHA concentration meets specifications | Passed | | Sterility | To ensure the product is sterile | Passed | | Bacterial Endotoxins | To confirm the endotoxins count in the device meets specifications | Passed | | pH | To confirm the pH of the gel meets specifications | Passed | | Residual crosslinker content | To confirm the residual crosslinker content of the gel meets specifications | Passed | | Mepivacaine content | To confirm the mepivacaine concentration of the gel meets specifications | Passed | | Impurities deriving from mepivacaine hydrochloride for RHA® Redensity™ Mepi | To confirm impurities in the gel meet specifications | Passed | | Extrusion force | To confirm the extrusion force meets specifications | Passed | | Rheology: mechanical properties of the gel | To confirm phase angle δ of the gel meets specifications | Passed | | Appearance of the device | To control visually the absence of irregularities and defects in the device | Passed | | Gel content | To ensure gel meets specifications | Passed | ### **B. Biocompatibility Studies** **Table 2: Summary of biocompatibility studies for RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi** | Test | Method | ISO Standard | Results | | --- | --- | --- | --- | | Cytotoxicity | In vitro mammalian cell culture test | ISO 10993-5 | Same cytotoxic potential as control*. | | Sensitization | Guinea pig maximization study | ISO 10993-10 | No delayed sensitization. | PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 5 {5} | Test | Method | ISO Standard | Results | | --- | --- | --- | --- | | Intracutaneous reactivity | Intradermal injection in rabbits. | ISO 10993-10 | Level of reactivity similar or slightly less than its control*. RHA® Redensity™ Mepi was non-irritant before Day 3. RHA®2 Mepi was non-irritant at 15 days. RHA®4 Mepi was non-irritant at 20 days. | | Pyrogenicity | Rabbit | | Non-pyrogenic. | | Genotoxicity | Ames test (bacterial reverse mutation study) | ISO 10993-3 | Non-mutagenic | | Genotoxicity | Mouse lymphoma assay | ISO 10993-3 | Non- mutagenic. | | Genotoxicity | Mouse peripheral blood micronucleus test | ISO 10993-3 | Non-genotoxic. | | Acute systemic toxicity | Mice intraperitoneal study | ISO 10993-11 | No evidence of acute systemic toxicity. | | Sub-acute and subchronic systemic toxicity | Intradermal injection in Sprague-Dawley | ISO 10993-11 | There was no evidence of systemic toxicity after 4 weeks and 13 weeks of implantation. | | Intradermal implantation | Intradermal implantation in rats | ISO 10993-6 | The test article was classified as non-irritant. No adverse response microscopically or macroscopically. After 52 weeks, degradation had started. | (*) Note: The control device was an FDA approved Hyaluronic Acid soft tissue filler, with similar characteristics. The control for RHA® Redensity™ Mepi was RHA® Redensity™, for RHA®2 Mepi was RHA®2 and for RHA®4 Mepi was RHA®4. Some testing performed with RHA®2 Mepi and RHA®4 Mepi is applicable to RHA®3 Mepi The 4 and 13 weeks systemic toxicity studies did not evidence signs of systemic toxicity after short or medium term exposure of RHA® Redensity™ Mepi, RHA®2 Mepi and RHA®4 Mepi. Extensive literature review of the materials used for the manufacturing of RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi concluded that no studies or reports were found indicating that the materials or their degradation products should pose a significant risk of chronic systemic toxicity in animals or humans. Therefore, there was no biological risks associated with chronic systemic toxicity. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 6 {6} The tumorigenic potential of RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi was not considered to be a biological risk based on the following data: - The three-test battery of genotoxicity carried out on RHA® Redensity™ Mepi, RHA®2 Mepi, and RHA®4 Mepi demonstrated that the three formulations were not genotoxic. Results are applicable to RHA®3 Mepi. - Absence of known toxicological concerns related to genotoxicity and/or carcinogenicity regarding hyaluronic acid. - While the crosslinker (BDDE) is known to be mutagenic and associated with tumor formation in mice in one study, based on the residual amount of BDDE in the finished product, Teoxane concluded that the carcinogenicity risk related to the presence of the BDDE in RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi was negligible. ### C. Additional Studies Stability data of RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi have been collected for 24 month period at 25°C ± 2°C and 60% ± 5% relative humidity. At each time point, product was characterized via microbiological, physical, chemical, mepivacaine hydrochloride content, and mepivacaine-related degradant parameters. Conformity of real-time aged product with all specifications was confirmed. ### X. SUMMARY OF PRIMARY CLINICAL STUDIES #### Overview of Safety and Effectiveness Clinical Studies RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi, and RHA®4 Mepi are strictly identical to approved dermal filler RHA® Redensity™, RHA®2, RHA®3, and RHA®4, respectively, except for the small amount of anesthetic medicine they contain: RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi, and RHA®4 Mepi contain 0.3% w/w of mepivacaine while RHA® Redensity™, RHA®2, RHA®3, and RHA®4 contain 0.3% w/w of lidocaine. Both anesthetics, mepivacaine and lidocaine, are of the same family with the same mechanisms of effects and overall safety profiles. RHA® Redensity™ Mepi and RHA® Redensity™ are injected in the same location and have the exact same indication. RHA®2, RHA®3, RHA®2 Mepi and RHA®3 Mepi are injected in the same location, into the mid-to-deep dermis and have the exact same indication. RHA®4 and RHA®4 Mepi are injected in the same location, both into the deep dermis to superficial subcutaneous and have the exact same indication. For all products, the anesthetic is released from the gel within approximately 24 hours and the anesthetic effect lasts for an average of 3 to 4 hours. Accordingly, the long term safety and effectiveness conclusions that were drawn for RHA® Redensity™, RHA®2, RHA®3, and RHA®4, were leveraged to support the long term safety and effectiveness of RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi, and RHA®4 Mepi. The safety and effectiveness conclusions for RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi, and RHA®4 Mepi, were extrapolated from clinical studies as follows: PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 7 {7} - The long term safety and effectiveness of RHA® Redensity™ Mepi were evaluated in a clinical study of RHA® Redensity™. - The long-term safety and effectiveness of RHA®2 Mepi and RHA®3 Mepi were evaluated in a clinical study using RHA®2 and RHA®3, respectively. - The long-term safety and effectiveness of RHA®4 Mepi were evaluated in a clinical study using RHA®4. These clinical studies are summarized below: #### **A. Safety and Effectiveness of RHA® Redensity™ Mepi** The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of injection into the dermis and superficial dermis of the face with RHA® Redensity™, for correction of moderate to severe dynamic perioral rhytids, in adults aged 22 years or older. The safety data of this clinical study are presented in the SSED available on the CDRH website under approved supplement P170002/S012 on December 22, 2021. #### **B. Safety and Effectiveness of RHA® 2 Mepi, RHA®3 Mepi and RHA®4 Mepi** The applicant performed two clinical studies to establish a reasonable assurance of safety and effectiveness of injection into the mid to deep dermis with RHA®2 and RHA®3 under IDE G140028 (Study 1302) or deep dermis to superficial subcutaneous tissue with RHA®4 under IDE G140106 (Study 1402) for the correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds (NLFs) in adults aged 22 years or over. Data from these clinical studies were the basis for the original PMA approval decision for RHA®2, RHA®3 and RHA®4. The safety data of these two clinical studies are presented in the SSED available on CDRH website under original approval of P170002 on October 19, 2017. #### Overview of Clinical Studies to Evaluate Reduction in Pain Two clinical studies were performed to demonstrate non-inferiority of pain reduction for the mepivacaine-containing devices (RHA® Redensity™ Mepi, RHA®2 Mepi, RHA®3 Mepi, and RHA®4 Mepi) when compared to the respective lidocaine-containing devices (RHA® Redensity™, RHA®2, RHA®3, and RHA®4): - The applicant performed a clinical study to demonstrate the non-inferiority of RHA® Redensity™ Mepi to RHA® Redensity™ in terms of reducing pain at time of injection when injected into the perioral rhytids under IDE G190055. A summary of the clinical study is presented below, beginning in part C. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 8 {8} - The applicant performed a clinical study to demonstrate the non-inferiority of RHA$^{®}$4 Mepi to RHA$^{®}$4 in terms of reducing pain at time of injection when injected into the nasolabial folds under IDE G190118. Due to similarities in the formulation of RHA$^{®}$2 Mepi, RHA$^{®}$3 Mepi, and RHA$^{®}$4 Mepi, results of the clinical study evaluating pain reduction of RHA$^{®}$4 Mepi (G190118) were leveraged to demonstrate non-inferiority of RHA$^{®}$2 Mepi and RHA$^{®}$3 Mepi in terms of reducing pain at time of injection. A summary of the clinical study is presented, below beginning in part G. ### C. Study Design for RHA$^{®}$ Redensity$^{™}$ Mepi for Study G190055 to Evaluate Effectiveness of RHA$^{®}$ Redensity$^{™}$ Mepi in Reducing Pain The applicant performed an additional clinical study to demonstrate the safety and effectiveness of RHA$^{®}$ Redensity$^{™}$ Mepi under IDE G190055. The purpose of this clinical study was to compare RHA$^{®}$ Redensity$^{™}$ Mepi containing mepivacaine with RHA$^{®}$ Redensity containing lidocaine in terms of reducing pain during injection into the perioral rhytids. The goal was to show that RHA$^{®}$ Redensity$^{™}$ Mepi was non inferior to RHA$^{®}$ Redensity$^{™}$ in reducing pain as felt by the subject during injection assessed immediate after injection of each side using a 100 mm Visual Analog Scale (VAS). The duration of the effectiveness of the anesthetic agent (mepivacaine or lidocaine) is less than a day. The study lasted 30 days. Subjects in IDE G190055 were treated between October 30, 2019 and January 22, 2020. The database reflected data collected for 30 subjects who were randomized and completed the study. There were three U.S. investigational sites. The clinical study was a randomized, double blinded, within-subject (split-face) study in which the perioral rhytids of one side of the mouth were injected with RHA$^{®}$ Redensity$^{™}$ Mepi and the perioral rhytids on the other side of the mouth were injected with the control device RHA$^{®}$ Redensity$^{™}$ (with lidocaine). The primary effectiveness objective was to demonstrate the non-inferiority of RHA$^{®}$ Redensity$^{™}$ Mepi (with mepivacaine) versus the control (RHA$^{®}$ Redensity$^{™}$ with lidocaine) in terms of reducing pain during device injection into the perioral rhytids. Primary endpoint was injection site pain felt during injection of one side of the mouth assessed by the subject immediately following injection with RHA$^{®}$ Redensity$^{™}$ Mepi (with mepivacaine), compared to the injection site pain felt during injection into the contralateral side of the mouth assessed immediately following injection with RHA$^{®}$ Redensity$^{™}$ with lidocaine. RHA$^{®}$ Redensity$^{™}$ Mepi and RHA$^{®}$ Redensity$^{™}$ are completely identical except for 0.3% mepivacaine replacing 0.3% lidocaine. The study duration was 4 weeks and could be extended to 8 weeks for subjects who presented an unresolved clinically significant device related Adverse Event. Subjects received treatment for their perioral rhytids with RHA$^{®}$ Redensity$^{™}$ Mepi on one side and RHA$^{®}$ Redensity$^{™}$ (the control) on the other side of their mouth. The order of injection and the side were assigned randomly. To minimize potential interference between the effect of the anesthetic agents of each study device, left and right perioral areas were separated by a “no treatment zone” defined as the area between the philtral columns (approximately 8 mm). Similarly, a no treatment zone of the lower perioral area was defined as the ~8 mm area directly below the upper perioral no treatment zone. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 9 {9} Subjects assessed their pain at time of injection and several times up to 60 minutes post injection using a 100 mm Visual Analog Scale (VAS). Subjects reported their Common Treatment Responses on a 30-day diary and the duration of the anesthetic effect and returned 30 days later for a final Visit 2. The treating investigator performed effectiveness and safety assessments at each visit, including during a call 3 days after treatment. Subjects performed effectiveness and satisfaction assessments when compared to Baseline, prior to injection. The control group was the perioral area of the same subject injected with RHA® Redensity™ which has been approved for the same indication and is identical to RHA® Redensity™ Mepi except for the anesthetic in the formulation, wherein RHA® Redensity™ includes lidocaine and RHA® Redensity™ Mepi includes mepivacaine for pain reduction. RHA® Redensity™ is legally marketed in the United States. # 1. Key Clinical Inclusion and Exclusion Criteria Enrollment in the pivotal study G190055 was limited to subjects who met the following key inclusion criteria: - Outpatient, male or female of any race, 22 years of age or older. - Moderate to severe perioral rhytids of grade 2 or 3 on the four-point Perioral Rhytid Severity Rating Scale (PR-SRS) (ranging from 0-3). - Perioral rhytids of the same PR-SRS grade on the left and right sides of the mouth. - Willing to abstain from facial aesthetic procedures/therapies that could interfere with study evaluations for the duration of the study. - Able to follow study instructions and complete all required visits. Patients were not permitted to enroll in the study if they met any of the following key exclusion criteria: - Female subjects who were pregnant, breast-feeding, or of childbearing potential and not practicing reliable birth control. - Known hypersensitivity or previous allergic reaction to any component of the study devices. - Use of a prohibited treatment/procedure within certain time periods. - Known sensitivity to local anesthetics of the amide type, history of multiple severe allergies, or history of anaphylactic shock. - Known susceptibility to keloid formation, hypertrophic scarring or clinically significant skin pigmentation disorders (Treating Investigator (TI) discretion). - Clinically significant active skin disease within 6 months prior to study entry (TI discretion). - History of active chronic debilitating systemic disease that in the opinion of the investigator, would make the subject a poor candidate in the study. - History of connective tissue disease. - Malignancy (excluding non-melanoma skin cancer) within the past 5 years. - Need for clinically significant (TI discretion) and continuous medical treatment within 2 weeks prior to initial visit. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 10 {10} - History or presence of condition or feature that may confound the interpretation of the results in the perioral region, for example, tattoo, significant facial hair, acne scaring, prior surgery in the area, potential for active disease or infection flare up such as herpes simplex. - Herpes simplex lesion flare-ups greater than 6 per year. - History of skin cancer in the treatment area - Elective, clinically significant facial procedures that may confound the interpretation of the results in the perioral region prior to study enrollment. - Clinically active disease or infection in the perioral area or mouth (e.g., dental abscess). - Subjects with known prolonged bleeding times because of disease or medication. - Medical or psychiatric conditions that may increase the risk associated with study participation or may interfere with the interpretation of study results or compliance of the subject and would make the subject inappropriate for entry into this study. - Have dentures or any device covering all or part of the upper palate, and/or severe malocclusion, dentofacial or maxillofacial deformities, or significant asymmetry of the perioral area. - Subjects seeking lip augmentation. - Exposure to any other investigational drug/device within 90 days of entering the study. - Clinically significant alcohol or drug abuse, or history of poor cooperation or unreliability. ## 2. Follow-up Schedule At Visit 1, RHA® Redensity Mepi with mepivacaine was administered in the perioral area in a randomly selected sequence (first or second injection) and side of the mouth and RHA® Redensity™ with lidocaine was administered in the perioral area to the other side. Both upper perioral rhytids were quadrants injected first, prior to injection of either lower perioral rhytids quadrants. Injection into the lower quadrants was only to improve cosmetic results. Immediately after injection of an upper perioral quadrant, subjects rated injection site pain experienced **during injection** using a 100 mm Visual Analog Scale (VAS). Injection site pain in each side of the mouth was also assessed at 15, 30, 45 and 60 minutes after the upper quadrant was injected. Additionally, subjects assessed anesthetic sensation on each side of the face every hour until normal sensation returned; the time for return to normal sensation was recorded. Subjects attended Visit 2 (30 days post-injection) where effectiveness and safety assessments were conducted. Subjects who presented with an unresolved clinically significant device related Adverse Event (AE) at Visit 2 received the optional follow-up phone call no later than 30 days after Visit 2. If the clinically significant AE remained unresolved, the Investigator requested that the subject attend the optional in-clinic follow-up visit (i.e., Visit 3) within 5 working days. Follow-up of the clinically significant AE continued until the AE was resolved or the TI determined that additional follow-up was not necessary. At study exit (i.e., Visit 2, optional follow-up phone call, or Visit 3), subjects were offered treatment with a commercially available dermal filler approved for injection into the perioral rhytids if they presented with wrinkles/lines in the no-treatment zone. ## 3. Clinical Endpoints Injection site pain was measured on each side of the face during the injection (primary endpoint) as well as at 15, 30, 45 and 60 minutes post-injection. The duration of the anesthetic effect on each PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 11 {11} side of the face was also followed on the patient diary. Lip functionality testing was conducted pre- and post-injection and at each follow-up visit. It included: lip function, lip sensation and lip movement. For safety evaluations, post-injection Common Treatment Responses (CTRs) including visual disturbances were assessed on a 30-Day patient CTR diary. Assessment of visual disturbances (Snellen visual acuity, confrontational visual fields test and ocular) motility were assessed by the TI at each visit. CTRs that were present on the last day of diary entry, regardless of severity and duration, were automatically recorded as AEs. Adverse Events (AEs) were assessed by the TI at each visit and during a call 3 days after treatment. The TI assessed all AEs and recorded the description (sign, symptom, or diagnosis), duration, seriousness, severity, cause and relationship to the study device and action taken. For statistical analysis, the maximal severity reported for the AE was recorded, even if the AE presented as being less severe at some point during the event. The primary effectiveness objective was to demonstrate the non-inferiority of RHA® Redensity™ Mepi with mepivacaine versus the control (RHA® Redensity™ with lidocaine) in terms of reducing pain during device injection into the perioral area. Pain during injection was based on the 100 mm Visual Analog Scale (VAS), as assessed by subjects immediately after injection of each side. The primary effectiveness assessment consisted in comparing the injection site pain felt during injection of one perioral area upper quadrant assessed by the subject immediately following injection with RHA® Redensity™ Mepi (with mepivacaine) with the injection site pain felt during injection into the contralateral perioral area upper quadrant assessed immediately following injection with RHA® Redensity™ (with lidocaine). Statistical analysis of the primary endpoint was performed using paired one-sided tests, with a significance level of 0.05, either parametric or non-parametric as appropriate. Secondary effectiveness endpoints included the comparison of the PR-SRS severity on each side of the mouth and comparing them to Baseline using Teoxane validated 4-grade photonumeric scale measuring the severity of the Perioral Rhytids (Perioral Rhytids Severity Rating Scale) (see Table 3 and Figure 1 below). Other secondary effectiveness endpoints included the Subject FACE-Q Assessment (Perioral Rhytids domain) at Baseline and Visit 2, patient satisfaction assessment at Visit 1 after treatment and at Visit 2 and the Global Aesthetic Improvement (GAI) assessment by the subject and the TI at Visit 1 after treatment and at Visit 2. The total volume required to achieve Optimal Cosmetic Result (OCR) was also reported for each device. Teoxane validated and proprietary Perioral Rhytids Severity Rating Scale (PR-SRS) Table 3: Teoxane Perioral Rhytid Severity Rating Scale (PR-SRS) | Grade | Name | Description | | --- | --- | --- | | 0 | Absent | No lines | | 1 | Mild | Shallow lines | | 2 | Moderate | Deeper lines | | 3 | Severe | Deepest lines | PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 12 {12} **PR-SRS** Perioral Rhytids Severity Rating Scale TEOXANE INTERNATIONAL RESEARCH Absent** *No Lines*  **1** **Mild** *Shallow Lines*  **2** **Moderate** *Deeper Lines*  **3** **Severe** *Deepest Lines*  Produced by CANFIELD Scientific, Inc. v1.0 TSC 04-2016 © 2016 Teoxane SA **Figure 1: Teoxane PR-SRS scale** PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 13 {13} #### **D. Accountability of PMA Cohort for RHA® Redensity™ Mepi for Study G190055** At the time of the database lock, the 30 subjects who were randomized and enrolled, all (100%) completed the study. Each subject was injected with RHA® Redensity™ Mepi in one side of the perioral area and RHA® Redensity™ in the other side of the perioral area. There were no subjects who dropped out or were lots to follow-up prior to the final study visit. There were no major protocol deviations reported in the study. As such, the intent to treat (ITT) and per protocol (PP) populations consisted of all randomized/enrolled subjects (i.e. n=30). The Safety (SAFT) population consisted of all study subjects that were randomized and received treatment with at least one of study device, i.e. n=30. #### **E. Study Population Demographics and Baseline Parameters for Study G190055** Subjects had a mean age of 64.3 years, an average BMI of 26.3, and all subjects were female and Caucasian. Fitzpatrick skin types were represented with 76.7% of subjects having skin types I-III, and 23.3% of subjects having skin types IV. Fitzpatrick skin types V and VI were not represented. Fitzpatrick skin type is a classification intended to reflect individual sun sensitivity and not race or phenotypic features. Ethnicity was well represented with 36.7% of subjects identifying as Hispanic or Latino and 63.3% as Non-Hispanic or Latino. **Table 4: Demographic characteristics at Baseline** | Demographic Variable | n=30 | | --- | --- | | **Age (years)** | | | N | 30 | | Mean ± SD [95% CIs] | **64.3 ± 8.2 [61.2, 67.3]** | | Median (P25, P75) | **65.5 (57.2, 71.0)** | | Min, Max | **48.0 - 78.0** | | Missing values | 0 | | **BMI (kg/m^{2})** | | | N | 30 | | Mean ± SD [95% CIs] | 26.3 ± 4.6 [24.6, 28.0] | | Median (P25, P75) | 25.5 (24.2, 29.7) | | Min, Max | 17.4 - 34.3 | | Missing values | 0 | | **Gender** | | | N | 30 | | Male | 0 (0.0%) | | Female | 30 (100%) | | Missing values | 0 | | **Race** | | | N | 30 | | Caucasian | 30 (100%) | | Black or African American | 0 (0.0%) | | American Indian or Alaska Native | 0 (0.0%) | | Asian | 0 (0.0%) | | Nat. Hawaiian, Other Pacific Islander | 0 (0.0%) | | Other | 0 (0.0%) | | Missing values | 0 | | **Ethnicity** | | | N | 30 | | Hispanic or Latino | 11 (36.7%) | | Non-Hispanic or Latino | 19 (63.3%) | PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 14 {14} | Demographic Variable | n=30 | | --- | --- | | Unknown | 0 (0.0%) | | Missing values | 0 | | Fitzpatrick Skin Type | | | N | 30 | | I-III | 23 (76.7%) | | I | 1 (3.3%) | | II | 11 (36.7%) | | III | 11 (36.7%) | | IV-VI | 7 (23.3%) | | IV | 7 (23.3%) | | V | 0 (0.0%) | | VI | 0 (0.0%) | | Missing values | 0 | In the upper quadrants, the overall total mean volume of RHA® Redensity™ Mepi injected to achieve optimal correction results was 0.27 ± 0.09 ml. It was 0.27 ± 0.08 ml for RHA® Redensity™. In the lower quadrants, the overall total mean volume of RHA® Redensity™ Mepi injected to achieve optimal correction results was 0.23 ± 0.13 ml. It was 0.22 ± 0.10 ml for RHA® Redensity™. ### F. Safety and Effectiveness Results for Study G190055 #### 1. Safety Results for Study G190055 The analysis of safety was based on the Safety cohort of 30 subjects who were randomized and all completed the study. The Common Treatment Responses for this study are presented below in Table 5 and Table 6. Safety of RHA® Redensity™ Mepi was evaluated through a 30-day patient Common Treatment Response (CTR) diary which was completed after the injection individually for each side of the mouth, AE assessments at each visit, lip functionality and visual disturbances before and after injection and at each visit and measurement of injection site pain at time of injection and up to 60 minutes after injection for each side of the face. #### Common Treatment Responses (CTR) A total of 25 (83.3%) and 24 (80.0%) of the 30 subjects in the RHA® Redensity™ Mepi and RHA® Redensity™ groups, respectively, experienced at least one CTR. The proportions of subjects experiencing at least one CTR of each category (e.g., Bruising, Lumps/Bumps, etc.) was similar between treatment groups with the majority (220/226, 97.4%) of CTRs resolving in 14 days or fewer. Of the 226 CTRs that occurred following study treatments (including the CTRs reported in the “other” CTR category by the subjects), 220 (97.4%) had a cumulative duration of 14 days or less (i.e., 141 [62.4%] 1-3 days, 60 [26.5%] 4-7 days, and 19 [8.4%] 8-14 days). Six (2.7%) CTRs had a cumulative duration of 15-30 days (i.e., 2 [0.9%] 15-21 days and 4 [1.8%] 22-30 days). PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 15 {15} Five (5) CTRs from three (3) subjects were recorded on the last day of the diary, and each was elevated to a Treatment-Related AE. In total, 3 (10.0%) and 2 (6.7%) subjects in the RHA® Redensity™ Mepi and RHA® Redensity™ groups recorded CTRs on the last day of the diary. Specifically, on the last day of the CTR diary: - 2 subjects reported firmness with RHA® Redensity™ Mepi and RHA® Redensity™ - 1 subject reported lumps/bumps with RHA® Redensity™ Mepi On the last day of the diary when they were automatically elevated to Treatment-Related AEs (TRAEs), all CTRs were mild in severity and deemed by the Investigators to be not clinically significant. Two subjects recorded symptoms in the “other” CTR category, which were processed as AEs. Specifically: - One subject experienced injection site soreness on both sides of the mouth of moderate severity. Both events resolved within 2 days. - One subject experienced needle marks on both sides of the mouth that were of mild severity. Both resolved within 4 days. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 16 {16} **Table 5: CTRs by Duration** | CTR | Group | ≥1 CTR | Cumulative Duration (days) | | | | | CTR Last Day Diary | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | 1-3 | 4-7 | 8-14 | 15-21 | 22-30 | | | At least 1 CTR | RHA® Redensity™ Mepi | 24 (80.0%) | - | - | - | - | - | 3 (10.0%) | | | RHA® Redensity™ | 25 (83.3%) | - | - | - | - | - | 2 (6.7%) | | Bruising | RHA® Redensity™ Mepi | 12 (40.0%) | 4 (13.3%) | 7 (23.3%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 16 (53.3%) | 3 (10.0%) | 11 (36.7%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Discoloration | RHA® Redensity™ Mepi | 10 (33.3%) | 7 (23.3%) | 3 (10.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 10 (33.3%) | 7 (23.3%) | 3 (10.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Firmness | RHA® Redensity™ Mepi | 14 (46.7%) | 9 (30.0%) | 2 (6.7%) | 1 (3.3%) | 1 (3.3%) | 1 (3.3%) | 2 (6.7%) | | | RHA® Redensity™ | 19 (63.3%) | 11 (36.7%) | 4 (13.3%) | 2 (6.7%) | 1 (3.3%) | 1 (3.3%) | 2 (6.7%) | | Itching | RHA® Redensity™ Mepi | 4 (13.3%) | 3 (10.0%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 2 (6.7%) | 1 (3.3%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Lumps/Bumps | RHA® Redensity™ Mepi | 15 (50.0%) | 11 (36.7%) | 3 (10.0%) | 0 (0.0%) | 0 (0.0%) | 1 (3.3%) | 1 (3.3%) | | | RHA® Redensity™ | 17 (56.7%) | 5 (16.7%) | 8 (26.7%) | 3 (10.0%) | 0 (0.0%) | 1 (3.3%) | 0 (0.0%) | | Pain | RHA® Redensity™ Mepi | 3 (10.0%) | 2 (6.7%) | 0 (0.0%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 4 (13.3%) | 3 (10.0%) | 0 (0.0%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Redness | RHA® Redensity™ Mepi | 16 (53.3%) | 11 (36.7%) | 2 (6.7%) | 3 (10.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 15 (50.0%) | 9 (30.0%) | 5 (16.7%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Swelling | RHA® Redensity™ Mepi | 21 (70.0%) | 17 (56.7%) | 2 (6.7%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 19 (63.3%) | 14 (46.7%) | 3 (10.0%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Tenderness | RHA® Redensity™ Mepi | 13 (43.3%) | 11 (36.7%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 12 (40.0%) | 10 (33.3%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Other (Needle track marks) † | RHA® Redensity™ Mepi | 1 (3.3%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 1 (3.3%) | 0 (0.0%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Other (Injection site Soreness) †† | RHA® Redensity™ Mepi | 1 (3.3%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 1 (3.3%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | † As these events were written into the CTR diary as “other” it was processed as AEs and was not subject to CTR reporting rules for AEs (i.e., elevation to AEs if present on the last day of the diary). Out of the 226 reported CTRs, severity was reported as “Mild” or “Moderate” for 218 (96.5%), with 8 (3.5%) CTRs rated by subjects as “Severe”. For most of those, the subjects reported those CTRs to be severe on both sides. None of the CTRs reported “Severe” by the subject were considered to be an Adverse Event by the Investigator and they all resolved within 30-days. The CTRs that were still present on the last day of the diary were all reported mild by the subject. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 17 {17} **Table 6: CTRs by Severity** | CTR | Group | ≥1 CTR | Maximum Severity within 30 Days | | | | | --- | --- | --- | --- | --- | --- | --- | | | | | None | Mild | Moderate | Severe | | At least 1 CTR | RHA® Redensity™ Mepi | 24 (80.0%) | 6 (20.0%) | 14 (46.7%) | 9 (30.0%) | 1 (3.3%) | | | RHA® Redensity™ | 25 (83.3%) | 5 (16.7%) | 13 (43.3%) | 10 (33.3%) | 2 (6.7%) | | Bruising | RHA® Redensity™ Mepi | 12 (40.0%) | 18 (60.0%) | 9 (30.0%) | 3 (10.0%) | 0 (0.0%) | | | RHA® Redensity™ | 16 (53.3%) | 14 (46.7%) | 9 (30.0%) | 6 (20.0%) | 1 (3.3%) | | Discoloration | RHA® Redensity™ Mepi | 10 (33.3%) | 20 (66.7%) | 8 (26.7%) | 2 (6.7%) | 0 (0.0%) | | | RHA® Redensity™ | 10 (33.3%) | 20 (66.7%) | 9 (30.0%) | 1 (3.3%) | 0 (0.0%) | | Firmness | RHA® Redensity™ Mepi | 14 (46.7%) | 16 (53.3%) | 11 (36.7%) | 3 (10.0%) | 0 (0.0%) | | | RHA® Redensity™ | 19 (63.3%) | 11 (36.7%) | 16 (53.3%) | 3 (10.0%) | 0 (0.0%) | | Itching | RHA® Redensity™ Mepi | 4 (13.3%) | 26 (86.7%) | 4 (13.3%) | 0 (0.0%) | 0 (0.0%) | | | RHA® Redensity™ | 2 (6.7%) | 28 (93.3%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | | Lumps/Bumps | RHA® Redensity™ Mepi | 15 (50.0%) | 15 (50.0%) | 12 (40.0%) | 3 (10.0%) | 0 (0.0%) | | | RHA® Redensity™ | 17 (56.7%) | 13 (43.3%) | 10 (33.3%) | 7 (23.3%) | 0 (0.0%) | | Pain | RHA® Redensity™ Mepi | 3 (10.0%) | 27 (90.0%) | 2 (6.7%) | 0 (0.0%) | 1 (3.3%) | | | RHA® Redensity™ | 4 (13.3%) | 26 (86.7%) | 3 (10.0%) | 0 (0.0%) | 1 (3.3%) | | Redness | RHA® Redensity™ Mepi | 16 (53.3%) | 14 (46.7%) | 12 (40.0%) | 3 (10.0%) | 1 (3.3%) | | | RHA® Redensity™ | 15 (50.0%) | 15 (50.0%) | 9 (30.0%) | 5 (16.7%) | 1 (3.3%) | | Swelling | RHA® Redensity™ Mepi | 21 (70.0%) | 9 (30.0%) | 16 (53.3%) | 4 (13.3%) | 1 (3.3%) | | | RHA® Redensity™ | 19 (63.3%) | 11 (36.7%) | 11 (36.7%) | 7 (23.3%) | 1 (3.3%) | | Tenderness | RHA® Redensity™ Mepi | 13 (43.3%) | 17 (56.7%) | 11 (36.7%) | 1 (3.3%) | 1 (3.3%) | | | RHA® Redensity™ | 12 (40.0%) | 18 (60.0%) | 10 (33.3%) | 2 (6.7%) | 0 (0.0%) | | Other (Needle track marks) | RHA® Redensity™ Mepi | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 1 (3.3%) | 0 (0.0%) | | | RHA® Redensity™ | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 1 (3.3%) | 0 (0.0%) | | Other (Injection Site Soreness) | RHA® Redensity™ Mepi | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 1 (3.3%) | 0 (0.0%) | | | RHA® Redensity™ | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 1 (3.3%) | 0 (0.0%) | The TI reviewed all CTRs to ensure they were elevated as appropriate to the status of an AE. CTRs were not considered AEs unless the duration and/or severity were in excess of that typically observed following injection of a dermal filler and were clinically significant as determined by the TI. However, CTRs that were noted on the last day of the CTR diary were recorded automatically as AEs regardless of their severity (30-day rule). Overall, for CTRs that were automatically PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 18 {18} elevated to the level of an AE after 30 days, the TI determined that none of the AEs were of “severe” intensity. # Treatment Related Adverse Events (TRAEs) All Treatment-Related Adverse Events (TRAEs) were the types and frequency of events that are typically experienced following the injection of a dermal filler, 100% of them were based on CTR diary entries (Table 7). TRAEs were reported for 4 (4/30, 13.3%) subjects in the RHA® Redensity™ Mepi group and for 3 (10%) subjects in the RHA® Redensity™ group. The most common event was injection site induration which was experienced by 2 (2/30, 6.7%) subjects in each group. There were a total of 9 TRAEs as follows: - One subject reported injection site induration with RHA® Redensity™ Mepi and RHA® Redensity™ (i.e., two (2) TRAEs); - One subject reported injection site induration and injection site pain with RHA® Redensity™ Mepi and RHA® Redensity™ (i.e., four (4) TRAEs); - One subject reported needle track marks with RHA® Redensity™ Mepi and RHA® Redensity™ (i.e., two (2) TRAEs); - One subject reported injection site mass with RHA® Redensity™ Mepi (i.e., one (1) TRAE). Study Investigators deemed all TRAEs to be mild or moderate in severity and none were considered by Investigators to be clinically significant. All TRAEs resolved spontaneously without the need for medical therapy within 77 days. Importantly, except for injection site mass, all TRAEs occurred on both were bilateral, occurring on both sides of the subjects’ mouth. Table 7: Treatment-Related AEs Sorted by SOC and PT | TRAEs | | RHA® Redensity™ Mepi | | RHA® Redensity™ Mepi | | All | | | --- | --- | --- | --- | --- | --- | --- | --- | | SOC | PT | n=30 Subjects | Events | n=30 Subjects | Events | n=30 Subjects | Events | | Any TRAE | | 4 (13.3%) [4.4, 31.6] | 5 | 3 (10%) [2.6, 27.7] | 4 | 4 (13.3%) [4.4, 31.6] | 9 | | Gen. disorders and admin. site conditions | | 3 (10%) [2.6, 27.7] | 4 | 2 (6.7%) [1.2, 23.5] | 3 | 3 (10%) [2.6, 27.7] | 7 | | Injection site induration | | 2 (6.7%) [1.2, 23.5] | 2 | 2 (6.7%) [1.2, 23.5] | 2 | 2 (6.7%) [1.2, 23.5] | 4 | | Injection site mass | | 1 (3.3%) [0.2, 19.1] | 1 | 0 (0%) [--, --] | 0 | 1 (3.3%) [0.2, 19.1] | 1 | | Injection site pain | | 1 (3.3%) [0.2, 19.1] | 1 | 1 (3.3%) [0.2, 19.1] | 1 | 1 (3.3%) [0.2, 19.1] | 2 | | Injury, poisoning and proc. complications | | 1 (3.3%) [0.2, 19.1] | 1 | 1 (3.3%) [0.2, 19.1] | 1 | 1 (3.3%) [0.2, 19.1] | 2 | | Needle track marks | | 1 (3.3%) [0.2, 19.1] | 1 | 1 (3.3%) [0.2, 19.1%] | 1 | 1 (3.3%) [0.2, 19.1] | 2 | SAFT population 95% CI [xx.x, xx.x] Number of Participants (% in parenthesis). SOC=System Organ Class, PT=Preferred Term There were no AEs reported directly by the TI. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 19 {19} There were no late onset of TRAEs, and no events were deemed to be granuloma. There were no reports of serious TRAEs or Unexpected Adverse Device Effects, no visual disturbances, no deaths, and no subjects prematurely withdrew due to a Treatment-Related Adverse Event. Of the 9 reported TRAEs, the majority (8 events; 88.9%) occurred in 3 subjects where a linear threading injection technique was employed, while 1 (11.1%) TRAE was associated with a fan-like injection technique. Linear threading injection technique was used for only 10 (33.3%) subjects, yet was associated with 88.9% of TRAEs. However, the small sample size for this study (i.e., n=30) does not provide sufficient power to determine the association between injection technique and TRAEs. ### Lip Functionality Lip functionality was assessed by evaluation of lip movements and lip sensation. The mean proportion of words pronounced correctly at Visit 1 pre- and post-injection and at Visit 2 was 100%. Lip sensation (monofilament test) was assessed as per the proportion of touch-points that the subject could feel (based on a total of 3 touch-points per quadrant, subject blindfolded). The proportion of touch-points that subjects could feel at Visit 1 pre-injection and post-injection, and at Visit 2 was 100% for both treatment groups and in all quadrants. Lip sensation (cotton wisp test) was assessed as per the proportion of touch-points that the subject could feel (based on a total of 3 points per quadrant, subject blindfolded). The proportion of touch-points that subjects could feel at Visit 1 pre-injection and post-injection, and at Visit 2 was 100% for both treatment groups and in all quadrants ### 2. Effectiveness Results for Study G190055 #### Primary endpoint The analysis of effectiveness was based on the PP population. To achieve non-inferiority, the observed p-value must be $\leq 0.05$ (taking account of the non-inferiority margin). In case of non-inferiority, for achieving superiority of RHA® Redensity™ Mepi with mepivacaine over RHA® Redensity™ with lidocaine in terms of reducing pain, the observed p-value must be $\leq 0.05$. The level of pain during injection was $25.0 \pm 25.68$ and $22.4 \pm 23.21$ in the RHA® Redensity™ Mepi and RHA® Redensity™ group, respectively. This resulted in a difference between groups of $-2.6 \pm 10.33$ (Table 8). As the p-value (non-inferiority $\delta = 10\text{mm}$) was $< 0.0001$, non-inferiority was achieved. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 20 {20} **Table 8: Injection Site Pain – Non-Inferiority – Primary Outcome\*** | | RHA® Redensity™ Mepi n=30 | RHA® Redensity™ Mepi n=30 | Difference** n=30 | | --- | --- | --- | --- | | N | 30 | 30 | 30 | | Mean ± SD | 25.0 (25.63) | 22.4 (23.21) | -2.6 (10.33) | | Median (P25, P75) | 20.0 (1.0, 39.0) | 18.0 (0.0, 31.0) | 0.0 (-4.0, 2.0) | | Min, Max | 0, 100 | 0, 86 | -27, 10 | | 95.0% CI | 14.4, 34.5 | 13.7, 31.1 | -6.4, 1.3 | | P-value (non-inferiority δ 10mm) | **<0.0002** | | | | P-value(superiority) | N/A*** | | | PP and ITT populations were identical \* During injection, upper perioral quadrants. \*\* If RHA® Redensity™ - RHA® Redensity™ Mepi<0, RHA® Redensity™ less painful than RHA® Redensity™ Mepi. If RHA® Redensity™ - RHA® Redensity™ Mepi>0, RHA® Redensity™ more painful than RHA® Redensity™ Mepi. \*\*\* Superiority not tested. ### **Pain at injection** Other timepoints for injection pain were measured and compared for up to 60 minutes post-injection; however, they were not tested for non-inferiority. By 15 minutes post-injection, injection pain was markedly reduced at 6.8±13.72 mm and 6.3±12.29 mm in the RHA® Redensity™ Mepi and RHA® Redensity™ group, respectively, and was totally absent by 60 minutes. There were no significant differences between treatment groups at any timepoint (Table 9). The duration of anesthetic effect was also similar between treatment groups. The duration of anesthetic effect was 3.6±3.62 hours and 3.0±2.10 in the RHA® Redensity™ Mepi and RHA® Redensity™ group, respectively (Table 10). Similar injection pain levels were reported between FST, ethnicity and age subgroups following RHA® Redensity™ Mepi and RHA® Redensity™ treatments. **Table 9: Injection Site Pain – Mean Pain** | Pain VAS (mm)* | RHA® Redensity™ Mepi n=30 | RHA® Redensity™ n=30 | Difference** n=30 | | --- | --- | --- | --- | | N | 30 | 30 | 30 | | 15 Min | 6.8 (13.72) | 6.3 (12.29) | -0.6 (2.16) | | 30 Min | 1.0 (4.19) | 1.0 (4.03) | -0.0 (0.18) | | 45 Min | 0.4 (2.37) | 0.3 (1.83) | -0.1 (0.55) | | 60 Min | 0.0 (0.00) | 0.0 (0.00) | 0.0 (0.00) | ITT Population (identical to PP population) Mean (Standard Deviation) \* During injection, upper perioral quadrants. \*\* If RHA® Redensity™ - RHA® Redensity™ Mepi<0, RHA® Redensity™ less painful than RHA® Redensity™ Mepi. If RHA® Redensity™ - RHA® Redensity™ Mepi >0, RHA® Redensity™ more painful than RHA® Redensity™ Mepi. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 21 {21} **Table 10: Duration of Anesthetic Effect** | | RHA^{®} Redensity™ Mepi n=30 | RHA^{®} Redensity™ n=30 | | --- | --- | --- | | N | 29 | 29 | | Mean (SD) | 3.59 (3.62) | 3.01 (2.10) | | Median (P25, P75) | 2.28 (1.88, 4.05) | 2.28 (1.93, 4.03) | | Min, Max | 0.9, 19.0* | 0.3, 10.1 | | 95% CI | 2.21, 4.97 | 2.21, 3.81 | | Missing values | 1 (3.3%) | 1 (3.3%) | ITT Population (identical to PP population) Mean (Standard Deviation) *Subject 02-1801-003 was an outlier with an anesthetic duration of 19 hour for the RHA$^{®}$ I-M treatment group* ### Secondary effectiveness analysis Secondary endpoints included PR-SRS grade by the TI, the assessment of Global Aesthetic Improvement (GAI) by the TI and the subject. Effectiveness endpoints included two patient reported outcome measures as Subject Satisfaction and FACE-Q. At Visit 1, the PR-SRS post-injection change from pre-injection was nearly the same between treatment groups with the RHA$^{®}$ Redensity™ Mepi and RHA$^{®}$ Redensity™ treatment groups posting reductions of -1.5±0.63 and -1.5±0.57, respectively. Similarly, at Visit 2 the RHA$^{®}$ Redensity™ Mepi and RHA$^{®}$ Redensity™ treatment groups posting reductions of -1.4±0.56 and -1.4±0.57, respectively, indicating no loss of effect at Month 1 post-injection. Responder rates were identical between treatment groups reaching 96.7%. No difference was observed in term of improvement on the PR-SRS between FST, ethnicity and age subgroups following RHA$^{®}$ Redensity™ Mepi and RHA$^{®}$ Redensity™ treatments. The assessment of aesthetic improvement (GAI) by the TI and the subjects were identical between RHA$^{®}$ Redensity™ Mepi and RHA$^{®}$ Redensity™. The proportion of subjects demonstrating improvement (improved or much improved) at Visit 2 was 100% in both treatment groups as assessed by the TI and the subjects. The FACE-Q score for the Perioral Rhytids domain on a scale of 0 to 100 was 12.5 and 13.0 at Visit 1 pre-injection for RHA$^{®}$ Redensity™ Mepi and RHA$^{®}$ Redensity™ respectively and 90.5 and 88.0 at Visit 2. Scores were similar between RHA$^{®}$ Redensity™ Mepi and RHA$^{®}$ Redensity™ before injection, after injection and at the last visit. The proportion of subjects who were Satisfied or Very Satisfied with study treatment at Visit 2 was 96.7% (29/30) in both treatment groups. One subject was 'Neither Satisfied nor Dissatisfied' with study treatment on either side of the face. ### 3. Subgroup Analyses for Study G190055 Treatment cohorts were stratified based on Fitzpatrick Skin Type (I-III vs IV), ethnicity (Hispanic vs Non-Hispanic) and age (≤59 and >59 years old). PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 22 {22} **Table 11: Subgroup analysis for RHA$^{®}$ Redensity$^{™}$ Mepi for subjects who experienced at least 1 Treatment-Related AE** | Subgroups | | RHA^{®} Redensity^{™} Mepi N=30 | RHA^{®} Redensity^{™} N=30 | | --- | --- | --- | --- | | Fitzpatrick Skin Type (FST) | FST I-III (n=23) | 2 (8.7%) | 1 (4.3%) | | | FST IV (n=7) | 2 (28.6%) | 2 (28.6%) | | | FST V-VI (n=0) | NA* | NA* | | Ethnicity | Hispanic (n=11) | 2 (18.2%) | 2 (18.2%) | | | Non-Hispanic (n=19) | 2 (10.5%) | 1 (5.3%) | | Age | ≤ 59 year old (n=10) | 1 (10%) | 1 (10%) | | | >59 year old (n=20) | 3 (15%) | 2 (10%) | \*: there were no subjects enrolled with FST V-VI. Common Treatment Reactions and Treatment-Related AE incidence rates were not negatively correlated with Fitzpatrick skin type IV, ethnicity and age. #### 4. Pediatric Extrapolation for Study G190055 In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population. #### **G. Study Design for RHA$^{®}$ 4 Mepi for Study G190118 to Evaluate Effectiveness of RHA$^{®}$4 Mepi in Reducing Pain** RHA$^{®}$2 Mepi, RHA$^{®}$3 Mepi and RHA$^{®}$4 Mepi are identical gels except for their level of crosslinking: RHA$^{®}$2 Mepi is the least crosslinked and RHA$^{®}$4 Mepi is the most crosslinked. All three dermal fillers are indicated to be injected into the dynamic wrinkles and folds such as nasolabial folds. An analysis of the data of the subject's self-assessment of pain at time of injection in the long-term studies with approved RHA$^{®}$2, RHA$^{®}$3 and RHA$^{®}$4 containing lidocaine (G140028 and G140106) showed that pain was slightly higher with the most crosslinked dermal filler RHA$^{®}$4. As RHA$^{®}$2 Mepi, RHA$^{®}$3 Mepi and RHA$^{®}$4 Mepi are identical to RHA$^{®}$2, RHA$^{®}$3 and RHA$^{®}$4 except for their anesthetic agent (RHA$^{®}$ Mepi family of products containing mepivacaine and RHA$^{®}$ family of products containing lidocaine), the pain results of the RHA$^{®}$ family of products are applicable to RHA$^{®}$ Mepi family of products. The clinical study was performed with the worst-case representative of the three levels of crosslinked dermal fillers: RHA$^{®}$4 Mepi. RHA$^{®}$4 Mepi is the most crosslinked of RHA$^{®}$2 Mepi, RHA$^{®}$3 Mepi and RHA$^{®}$4 Mepi, it is injected into the deeper layers of the dermis and subject reported pain assessment was slightly higher. The results of the study performed with RHA$^{®}$4 Mepi are applicable to RHA$^{®}$2 Mepi and RHA$^{®}$3 Mepi. The applicant performed this additional clinical study to demonstrate the safety and effectiveness of RHA$^{®}$4 Mepi under IDE G190118. The purpose of this short term clinical study was to compare RHA$^{®}$4 Mepi containing mepivacaine with RHA$^{®}$4 containing lidocaine in terms of reducing pain during injection into the nasolabial folds. The goal was to show that RHA$^{®}$4 Mepi was non inferior to RHA$^{®}$4 in reducing pain as felt by the subject during injection assessed immediate after injection PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 23 {23} of each side using a 100 mm Visual Analog Scale (VAS). The duration of the effectiveness of the anesthetic agent (mepivacaine or lidocaine) is less than a day. Subjects were treated between October 30, 2019 and January 14, 2020. The database reflected data collected through February 18, 2020 and included 30 subjects who were randomized and completed the study. There were three U.S. investigational sites. The clinical study was a randomized, double blinded, within-subject (split-face) study with the nasolabial fold of one side of the face injected with RHA®4 Mepi and the nasolabial fold (NLFs) of the other side injected with the approved control device RHA®4 (with lidocaine). The primary effectiveness objective was to demonstrate the non-inferiority of RHA®4 Mepi (with mepivacaine) versus the control (RHA®4 with lidocaine) in terms of reducing pain during device injection into the NLFs. Primary endpoint was injection site pain felt during injection of one NLF assessed by the subject immediately following injection with RHA®4 Mepi (with mepivacaine) compared to the injection site pain felt during injection into the contralateral NLF assessed immediately following injection with RHA®4 with lidocaine. RHA®4 Mepi and RHA®4 are completely identical except for 0.3% mepivacaine replacing 0.3% lidocaine. The clinical study was performed with RHA®4 Mepi as the representative product of the range of RHA®2 Mepi, RHA®3 Mepi and RHA®4 Mepi. Results are applicable to all 3 products. The study duration was 4 weeks and could be extended to 8 weeks for subjects who presented with an unresolved clinically significant device related Adverse Event. Subjects received treatment of their NLFs with RHA®4 Mepi on one side and RHA®4 (the control) on the other side of the face. Subjects assessed their pain at time of injection and several times up to 60 minutes post injection using a 100 mm Visual Analog Scale (VAS). Subjects reported their Common Treatment Responses on a 30-day diary and the duration of the anesthetic effect and returned 30 days later for a final Visit 2. The treating investigator performed effectiveness and safety assessments at each visit, including during a call 3 days after treatment. Subjects performed effectiveness and satisfaction assessments when compared to Baseline, prior to injection. The control group was the NLF of the same subject injected with RHA®4 which has been approved for the same indication and is identical to RHA®4 Mepi except for the anesthetic in the formulation, wherein RHA® 4 includes lidocaine and RHA®4 Mepi includes mepivacaine for pain reduction. RHA®4 is legally marketed in the United States. # 1. Key Clinical Inclusion and Exclusion Criteria Enrollment in pivotal study G190118 was limited to patients who met the following key inclusion criteria: - Outpatient, male or female of any race, 22 years of age or older. Female patients of childbearing potential must have a negative urine pregnancy test (UPT) at Visit 1 and practice a reliable method of contraception throughout the study. - Moderate to severe bilateral aging defects in the nasolabial area, with wrinkles classified as NLF-WSRS grade 3 or 4 (ranging from 1 to 5) - NLFs of the same NLF-WSRS grade on the left and right sides of the face (i.e., approximate bilateral symmetry); PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 24 {24} - Willing to abstain from facial aesthetic procedures/therapies that could interfere with the study evaluations (e.g., other soft tissue fillers, botulinum toxin injections (frontalis and glabella complex allowed), laser or chemical resurfacing, etc.) for the duration of the study. Patients were not permitted to enroll in the study if they met any of the following exclusion criteria: - • Known hypersensitivity or previous allergic reaction to any component of the study devices (e.g., gram positive bacterial proteins, hyaluronic acid, lidocaine, etc.); - • Known sensitivity to local anesthetics of the amide type, history of multiple severe allergies, history of anaphylactic shock; - • Known susceptibility to keloid formation, hypertrophic scarring or skin pigmentation disorders; - • Clinically significant (Investigator discretion) active skin disease within 6 months prior to study entry; - • History of active chronic debilitating systemic disease, including insulin or non-insulin dependent diabetes; - • History of connective tissue disease (rheumatoid arthritis, scleroderma, systemic lupus erythematosus); - • History of malignancy, excluding non-melanoma skin cancer, within the past 5 years; - • History of bleeding disorders; - • Need for continuous medical treatment within 2 weeks prior to Visit 1; - • Received/used a prohibited treatment/procedure within certain time periods; - • Exhibit a physical attribute(s) that may prevent assessment or treatment of NLFs such as excessive facial hair, traumatic or surgical facial scars, and/or excessive hyperpigmentation in the treatment areas; - • Elective, clinically significant facial procedures that may confound the interpretation of the results in the NLF area (TI discretion), prior to study enrollment; - • Herpes simplex lesion flare-ups greater than 6 per year; - • Clinically active disease or infection in the NLF area; - • Subjects with known prolonged bleeding times because of disease or medication. If on a drug or supplement that prolongs bleeding times (e.g., non-steroidal anti-inflammatory, anticoagulant, high-dose vitamin E, fish oil, corticosteroids), wait 14 days or until bleeding times return to normal before injecting. (Note: low dose 81mg/day acetylsalicylic acid (ASA) is permitted). - • Medical or psychiatric conditions that may increase the risk associated with study participation or may interfere with the interpretation of study results or compliance of the subject and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study; - • Clinically significant alcohol or drug abuse, or history of poor cooperation or unreliability; - • Exposure to any other investigational drug/device within 90 days of entering the study; - • A condition or be in a situation that may put the subject at significant risk, may confound the study results, or may significantly interfere with the subject's participation in the study. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 25 {25} ## 2. Follow-up Schedule At Visit 1, RHA®4 Mepi with mepivacaine was administered in a randomly selected sequence (first or second injection) and side of the face, and RHA®4 with lidocaine was administered to the other side. Immediately after injection of each side, subjects rated injection site pain experienced during injection using a 100 mm Visual Analog Scale (VAS). Injection site pain was also assessed at 15, 30, 45 and 60 minutes post-injection. Additionally, subjects assessed anesthetic sensation on each side of the face every hour until normal sensation returned; the time for return to normal sensation was recorded. Subjects attended Visit 2 (30 days post-injection) where efficacy and safety assessments were conducted. Subjects who presented with an unresolved clinically significant device related Adverse Event (AE) at Visit 2 received the optional follow-up phone call no later than 30 days after Visit 2. If the clinically significant AE remained unresolved, the Investigator requested that the subject attend the optional in-clinic follow-up visit (i.e., Visit 3) within 5 working days. Follow-up of the clinically significant AE continued until the AE was resolved or the TI determined that additional follow-up was not necessary. ## 3. Clinical Endpoints Injection site pain was measured on each side of the face during the injection (primary endpoint) as well as at 15, 30, 45 and 60 minutes post-injection. The duration of the anesthetic effect on each side of the face was also followed on the patient diary. For safety evaluations, post-injection Common Treatment Responses (CTRs) including visual disturbances were assessed on a 30-Day patient CTR diary. Assessment of visual disturbances (Snellen visual acuity, confrontational visual fields test and ocular) motility were assessed by the TI at each visit. CTRs that were present on the last day of diary entry, regardless of severity and duration, were automatically recorded as AEs. Adverse Events (AEs) were assessed by the TI at each visit and during a call 3 days after treatment. The TI assessed all AEs and recorded the description (sign, symptom, or diagnosis), duration, seriousness, severity, cause and relationship to the study device and action taken. For statistical analysis, the maximal severity reported for the AE was recorded, even if the AE presented as being less severe at some point during the event. The primary effectiveness objective was to demonstrate the non-inferiority of RHA®4 Mepi with mepivacaine versus the control (RHA®4 with lidocaine) in terms of reducing pain during device injection into the NLFs. Pain during injection was based on the 100 mm Visual Analog Scale (VAS), as assessed by subjects immediately after injection of each side. The primary effectiveness assessment consisted in comparing the injection site pain felt during injection of one NLF assessed by the subject immediately following injection with RHA®4 Mepi (with mepivacaine) with the injection site pain felt during injection into the contralateral NLF assessed immediately following injection with RHA®4 (with lidocaine). Statistical analysis of the primary endpoint was performed using paired one-sided tests, with a significance level of 0.05, either parametric or non-parametric as appropriate. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 26 {26} Secondary effectiveness endpoints included the comparison of the Nasolabial Fold Wrinkle Severity Rating Scale (NLF-WSRS) severity on each side of the face and comparing them to Baseline using Teoxane validated 5-grade photonumeric scale measuring the severity of the NLFs (Wrinkles Severity Rating Scale) (see Table 12 and Figure 2 below). Other secondary effectiveness endpoints included the Subject FACE-Q Assessment (NLF domain) at Baseline and Visit 2, patient satisfaction assessment at Visit 1 after treatment and at Visit 2 and the Global Aesthetic Improvement (GAI) assessment by the subject and the TI at Visit 1 after treatment and at Visit 2. The total volume required to achieve Optimal Cosmetic Result (OCR) was also reported for each device. Teoxane validated a proprietary Nasolabial Fold Wrinkle Severity Rating Scale (NLF-WSRS). **Table 12: Teoxane Nasolabial Fold Wrinkle Severity Rating Scale (NLF-WSRS)** | Grade | Name | Description | | --- | --- | --- | | 1 | Absent | No nasolabial fold, continuous skin line | | 2 | Mild | Shallow but visible fold, slight indentation | | 3 | Moderate | Moderately deep nasolabial fold, clear facial feature visible | | 4 | Severe | Very deep nasolabial fold, prominent 3 dimensional feature | | 5 | Extreme | Extremely deep and long nasolabial fold, skin redundancy | PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 27 {27} # NLF WSRS Nasolabial Folds Wrinkle Severity Rating Scale LABORATORIES TEOXANE WORSTAR 1 Absent    • No nasolabial fold • Continuous skin line 2 Mild    • Shallow but visible fold • Slight indentation 3 Moderate   • Moderately deep nasolabial fold • Clear facial feature visible  • Moderately deep nasolabial fold • Clear facial feature visible 4 Severe   • Very deep nasolabial fold • Prominent 3 dimensional feature  • Very deep nasolabial fold • Prominent 3 dimensional feature 5 Extreme   • Extremely deep and long nasolabial fold • Skin redundancy  Produced by CANFIELD Scientific, Inc. TTO 05-2014 © 2014 Teoxane SA Figure 2: Teoxane NLF-WSRS PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 28 {28} ## **H. Accountability of PMA Cohort for RHA® 4 Mepi for Study G190118** At the time of the database lock, the 30 subjects who were randomized and enrolled, all (100%) completed the study. Each subject was injected with RHA®4 Mepi in one NLF and RHA®4 in the other NLF. There were no subjects who dropped out or were lost to follow-up prior to the final study visit. There were no major protocol deviations reported in the study. As such, the ITT and PP populations consisted of all randomized/enrolled subjects (i.e. n=30). The Safety (SAFT) population consisted of all study subjects that were randomized and received treatment with at least one of study device, i.e. n=30. ## **I. Study Population Demographics and Baseline Parameters for Study G190118** Subjects had a mean age of 57.0 years and an average BMI of 28.1. The majority of subjects were female (90.0%). The majority of subjects identified as Caucasian (90.0%), with 10% of subjects identifying as Black or African American. Fitzpatrick skin types were well represented with 63.3% of subjects having skin types I-III, and 36.7% of subjects having skin types IV to VI (with 10% of subjects having skin types V/VI). Fitzpatrick skin type is a classification intended to reflect individual sun sensitivity and not race or phenotypic features. More than 36% of subjects in the study presented Fitzpatrick skin type IV to VI which is well representative of real-world experience as it is consistent with the American Society of Plastic Surgeons (ASPS) data: of the 13.3M cosmetic minimally invasive procedures that took place in 2020, 78% were for soft tissue fillers in Caucasian patients, 5% were in African-American, 5% in Asian/Pacific Islander, 10% in Hispanic and 1% in other patients. (https://www.plasticsurgery.org/documents/News/Statistics/2020/plastic-surgery-statistics-full-report-2020.pdf) **Table 13: Demographic characteristics at Baseline** | Demographic Variable | n=30 | | --- | --- | | **Age (years)** | | | N | 30 | | Mean (SD) [95% CIs] | 57.0 ± 9.7 [53.4, 60.6] | | Median (P25, P75) | 55.5 (52.0, 61.8) | | Min, Max | 33.0 – 79.0 | | Missing values | 0 | | **BMI (kg/m^{2})** | | | N | 30 | | Mean (SD) [95% CIs] | 28.1 ± 4.5 [26.5, 29.8] | | Median (P25, P75) | 27.6 (25.3, 29.5) | | Min, Max | 20.7 – 37.8 | | Missing values | 0 | | **Gender** | | | N | 30 | | Male | 3 (10.0%) | | Female | 27 (90.0%) | | Missing values | 0 | | **Race** | | | N | 30 | PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 29 {29} | Demographic Variable | *n=30* | | --- | --- | | Caucasian | 27 (90.0%) | | Black or African American | 3 (10.0%) | | American Indian, Alaska Native | 0 (0.0%) | | Asian | 0 (0.0%) | | Nat. Hawaiian, Pacific Islander | 0 (0.0%) | | Other | 0 (0.0%) | | Missing values | 0 | | **Ethnicity** | | | N | 30 | | Hispanic or Latino | 12 (40.0%) | | Not-Hispanic or Latino | 18 (60.0%) | | Missing values | 0 | | **Fitzpatrick Skin Type** | | | N | 30 | | **I-III** | **19 (63.3%)** | | I | 1 (3.3%) | | II | 8 (26.7%) | | III | 10 (33.3%) | | **IV-VI** | **11 (36.7%)** | | IV | 8 (26.7%) | | V | 0 (0.0%) | | VI | 3 (10.0%) | | Missing values | 0 | The overall total mean volume of RHA$^{®}$4 Mepi injected to achieve optimal correction results was 1.09 ± 0.31 ml. It was 1.08 ± 0.32 ml for RHA$^{®}$4. ## **J. Safety and Effectiveness Results for Study G190118** ### **1. Safety Results for Study G190118** The analysis of safety was based on the Safety cohort of 30 subjects who were randomized and all completed the study. The Common Treatment Responses for this study are presented below in Table 14 and Table 15. Safety of RHA$^{®}$4 Mepi was evaluated through a 30-day patient Common Treatment Response (CTR) diary which was completed after the injection individually for each side of the face, AE assessments at each visit, visual disturbances before and after injection and at each visit and measurement of injection site pain at time of injection and up to 60 minutes after injection for each side of the face. #### Common Treatment Responses (CTR) In both treatment groups, 29 of the 30 subjects (96.7%) experienced at least one CTR. The proportions of subjects experiencing at least one CTR of each category (e.g., Bruising, Lumps/Bumps, etc.) was similar between treatment groups with the majority of CTRs (292/320, 91.3%) resolving in 14 days or fewer. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 30 {30} Of the 320 CTRs that occurred following study treatments (including the CTRs reported in the “other” category by the subjects), 292 (91.3%) had a cumulative duration of 14 days or less (i.e., 142 [44.4%] 1-3 days, 88 [27.5%] 4-7 days, and 62 [19.4%] 8-14 days). There were 28 (8.8%) CTRs which had a cumulative duration of 15-30 days (i.e., 17 [5.3%] 15-21 days and 11 [3.4%] 22-30 days). Ten CTRs from 5 subjects were recorded on the last day of the diary, and each was automatically elevated to a Treatment-Related AE. In total, 5 (16.7%) and 4 (13.3%) subjects in the RHA®4 Mepi and RHA®4 groups recorded CTRs on the last day of the diary. Specifically, on the last day of the CTR diary: - One subject reported itching with RHA®4 Mepi and RHA®4, and firmness with RHA®4 - Three subjects reported firmness with RHA®4 Mepi and RHA®4 - One subject reported lumps/bumps with RHA®4 Mepi On the last day of diary when they were automatically elevated to Treatment-Related AEs (TRAEs), all CTRs were mild in severity. All TRAEs had resolved by the time of the study exit except the lumps/bumps for one subject. This event resolved spontaneously by day 46 post-injection without intervention. One subject recorded a symptom in the “other” category. Specifically, on subject experienced paresthesia on the corner of the mouth (on the side treated with RHA®4 Mepi) that was elevated to a Treatment-Related AE (i.e., paresthesia oral) that was of mild severity and which resolved in 2 days. PMA P170002/S026: FDA Summary of Safety and Effectiveness Data Page 31 {31} **Table 14: CTRs by Duration** | CTR | Group | ≥1 CTR | Cumulative Duration (days) | | | | | CTR Last Day Diary | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | | | 1-3 | 4-7 | 8-14 | 15-21 | 22-30 | | | At least 1 CTR | RHA^{®}4 Mepi | 29 (96.7%) | - | - | - | - | - | 5 (16.7%) | | | RHA^{®}4 | 29 (96.7%) | - | - | - | - | - | 4 (13.3%) | | Bruising | RHA^{®}4 Mepi | 19 (63.3%) | 8 (26.7%) | 5 (16.7%) | 5 (16.7%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | | | RHA^{®}4 | 21 (70.0%) | 9 (30.0%) | 8 (26.7%) | 4 (13.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Discoloration | RHA^{®}4 Mepi | 11 (36.7%) | 6 (20.0%) | 5 (16.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA^{®}4 | 12 (40.0%) | 7 (23.3%) | 3 (10.0%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Firmness | RHA^{®}4 Mepi | 24 (80.0%) | 5 (16.7%) | 4 (13.3%) | 9 (30.0%) | 1 (3.3%) | 5 (16.7%) | 3 (10.0%) | | | RHA^{®}4 | 22 (73.3%) | 2 (6.7%) | 6 (20.0%) | 6 (20.0%) | 6 (20.0%) | 2 (6.7%) | 4 (13.3%) | | Itching | RHA^{®}4 Mepi | 7 (23.3%) | 5 (16.7%) | 1 (3.3%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 1 (3.3%) | | | RHA^{®}4 | 6 (20.0%) | 4 (13.3%) | 1 (3.3%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 1 (3.3%) | | Lumps/Bumps | RHA^{®}4 Mepi | 22 (73.3%) | 8 (26.7%) | 2 (6.7%) | 9 (30.0%) | 1 (3.3%) | 2 (6.7%) | 1 (3.3%) | | | RHA^{®}4 | 21 (70.0%) | 5 (16.7%) | 4 (13.3%) | 6 (20.0%) | 5 (16.7%) | 1 (3.3%) | 0 (0.0%) | | Pain^{†} | RHA^{®}4 Mepi | 12 (40.0%) | 9 (30.0%) | 3 (10.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA^{®}4 | 9 (30.0%) | 7 (23.3%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Redness | RHA^{®}4 Mepi | 21 (70.0%) | 12 (40.0%) | 7 (23.3%) | 2 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA^{®}4 | 20 (66.7%) | 13 (43.3%) | 6 (20.0%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | Swelling | RHA^{®}4 Mepi | 21 (70.0%) | 9 (30.0%) | 7 (23.3%) | 5 (16.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | | | RHA^{®}4 | 23 (76.7%) | 10 (33.3%) | 8 (26.7%) | 4 (13.3%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | | Tenderness | RHA^{®}4 Mepi |…