RHA Redensity® Eye Lido; RHA Redensity® Eye

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION Device Generic Name: Injectable Dermal Filler Device Trade Name: RHA Redensity® Eye Lido and RHA Redensity® Eye Device Procode: LMH 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/S050 Date of FDA Notice of Approval: May 12, 2026 RHA Redensity® was approved on December 22, 2021, under PMA panel-track supplement P170002/S012 and RHA Redensity® Mepi was approved on October 13, 2023, under panel-track supplement P170002/S026. Both were approved for injection into the dermis and superficial dermis for the correction of moderate to severe dynamic perioral rhytids, in adults aged 22 years or older. The SSEDs to support the indication of RHA Redensity® and RHA Redensity® Mepi for the correction of moderate to severe perioral rhytids are available on the CDRH website and is incorporated by reference here. The current supplement was submitted to expand the indication of these two products. ## II. INDICATIONS FOR USE RHA Redensity® Eye Lido is indicated for injection into the sub-dermis and supraperiosteum for the correction of moderate to severe tissue volume deficiencies in the infraorbital region, in adults aged 22 years or older. RHA Redensity® Eye is indicated for injection into the sub-dermis and supraperiosteum for the correction of moderate to severe tissue volume deficiencies in the infraorbital region, in adults aged 22 years or older. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 1 {1} ### III. CONTRAINDICATIONS - RHA Redensity® Eye Lido and RHA Redensity® Eye are contraindicated for patients with severe allergies manifested by a history of anaphylaxis or history or presence of multiple severe allergies. - RHA Redensity® Eye Lido and RHA Redensity® Eye contain trace amounts of gram-positive bacterial proteins and is contraindicated for patients with a history of allergies to such material. - RHA Redensity® Eye Lido and RHA Redensity® Eye should not be used in patients with previous hypersensitivity to local anesthetics of the amide type, such as lidocaine or mepivacaine. - RHA Redensity® Eye Lido and RHA Redensity® Eye should not be used in patients with bleeding disorders. ### IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in RHA Redensity® Eye Lido and RHA Redensity® Eye labeling. ### V. DEVICE DESCRIPTION RHA Redensity® Eye Lido and RHA Redensity® Eye are viscoelastic, sterile, non-pyrogenic, clear, colorless, and biodegradable gel implants. They are produced with sodium hyaluronate (NaHA) with a concentration of 15 mg/g 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). RHA Redensity® Eye Lido contains 0.3% lidocaine hydrochloride monohydrate to reduce pain on injection. RHA Redensity® Eye contains 0.3% mepivacaine hydrochloride to reduce pain on injection. RHA Redensity® Eye Lido gel is pre-filled in a 1.0 ml syringe and is supplied with two 30G ½ inch hypodermic needles. RHA Redensity® Eye gel is pre-filled in a 1.0 ml syringe and is supplied with one 30G ½ inch hypodermic needle and one 25G 1 ½” cannula (with it 23G ¾” pre-hole needle). ### VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for tissue volume deficiencies in the infraorbital region: blepharoplasty that may include fat repositioning, fat grafting and different soft tissue fillers. These volume filling techniques can be used in conjunction with laser skin PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 2 {2} resurfacing or botulinum toxin to reduce wrinkles in the area. Each alternative has its own advantages and disadvantages. 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® products containing lidocaine have been sold in the United States since 2020 and RHA® products containing mepivacaine were launched late 2024. They have been approved for perioral rhytid and nasolabial fold indications. RHA® products with lidocaine are also commercially available in the European Union and registered in more than 45 countries around the world since 2015. They have been approved for a wide range of indications including for infraorbital hollows. No RHA® products containing lidocaine or mepivacaine have been removed from the marketplace for any reasons related to safety or effectiveness. ## 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® family of products, include 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. In addition to the common treatment responses noted above, the following adverse events were reported from use in the various locations of the face, as part of the post-marketing surveillance on the use of RHA® family of products in and outside the United States. The following adverse events were reported on the use of RHA family of products worldwide with a prevalence equal or superior to one occurrence for 100,000 syringes: skin edema, injection site masses (lumps and bumps), skin swelling, skin induration, vascular complication (such as vessel compression/occlusion), pain, ecchymosis, erythema, skin discoloration and inflammatory reaction. Also, the injection of a dermal filler in the infraorbital region may result in a Tyndall effect, i.e. temporary blue hue of the skin caused by light scattering onto the gel. Additionally, other less frequent adverse reactions have also been reported, including dermal filler overcorrection, allergic reaction, product misplacement, inflammatory nodules (papules), skin necrosis, granuloma, injection site movement impairment, paraesthesia, skin atrophy, injection site fibrosis, urticaria, device dislocation and injection site extravasation. Delayed-onset inflammation near the site of dermal filler injections is one of the known adverse events associated with dermal fillers. Cases of delayed-onset inflammation have been reported to occur at the dermal filler treatment site following viral or bacterial PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 3 {3} illnesses or infections, vaccinations, or dental procedures. Typically, the reported inflammation was responsive to treatment or resolved on its own. Additionally, the following rare but serious adverse events that are associated with intravascular injection of other soft tissue 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. In many cases the symptoms resolved without any treatment. Reported treatments included the use of (in alphabetical order): analgesics, antibiotics, antihistamines, anti-inflammatories, anti-viral, corticosteroids, drainage, excision, implant dissolution (hyaluronidase), incision, massage and vasodilators. Outcomes for these reported events ranged from resolved to ongoing at the time of last contact. For the specific adverse events that occurred in the clinical study, please see Section X below. ### IX. SUMMARY OF NON-CLINICAL STUDIES #### A. Laboratory Studies Table 1: Physical and Chemical Testing – Requirements for RHA Redensity® Eye Lido and RHA Redensity® Eye | 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 meet specifications | Passed | | Residual crosslinker content | To confirm the residual crosslinker content of the gel meets specifications | Passed | | Anesthetic content Lidocaine for RHA Redensity® Eye Lido Mepivacaine for RHA Redensity® Eye | To confirm the anesthetic concentration of the gel meets specifications | Passed | | Impurities deriving from anesthetic | 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 | PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 4 {4} # **B. Biocompatibility Studies** Table 2: Summary of Biocompatibility Studies for RHA Redensity® Eye Lido and RHA Redensity® Eye | Test | Method | ISO Standard or USP | Results | | --- | --- | --- | --- | | Cytotoxicity | MTS Cytotoxicity Test Agarose Overlay Method | ISO 10993-5 | Same cytotoxic potential as control*. | | Sensitization | Guinea pig maximization study | ISO 10993-10 | No delayed sensitization. | | Intracutaneous reactivity | Intradermal injection in rabbits | ISO 10993-10** | Level of reactivity similar or slightly less than its control*. RHA Redensity® Eye Lido was non-irritant at 4 days or sooner. RHA Redensity® Eye was non-irritant in 72 hours or sooner. | | Pyrogenicity | Rabbit pyrogen study | USP 36 NF 31 (RHA Redensity® Eye Lido) USP 41 NF 36 (RHA Redensity® Eye) ISO 10993-11 | Non-pyrogenic. | | Genotoxicity | Ames test (bacterial reverse mutation study) | ISO 10993-3 | Non-mutagenic. | | Genotoxicity | Mouse lymphoma assay (MLA) | ISO 10993-3 | Non- mutagenic. | | Genotoxicity | Mouse peripheral blood micronucleus test (for RHA Redensity® Eye Lido only) | ISO 10993-3 | Non-genotoxic. | | Acute systemic toxicity | Mice intraperitoneal study | ISO 10993-11 | No evidence of acute systemic toxicity. | | Subacute and subchronic systemic toxicity | Intradermal injection in Sprague-Dawley rats (for RHA Redensity® Eye Lido only) | ISO 10993-11 | No toxicological concern. | | 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 product is legally marketed with similar indications for use (**) Note: This standard has been updated in 2021 and now covers only sensitization tests, ISO 10993-23 is now covering irritation tests. However, in vivo intracutaneous tests were carried out based on a methodology which has not been modified. Therefore, results remain valid accordingly for irritation assays performed on RHA Redensity® Eye Lido and RHA Redensity® Eye products. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 5 {5} ### C. Stability studies Stability data have been collected on three batches per product (RHA Redensity® Eye Lido and RHA Redensity® Eye) at 25°C ± 2°C and 60% ± 5% relative humidity (ICH long term storage conditions). The stability study was conducted through 36 months for RHA Redensity® Eye Lido and 24 months for RHA Redensity® Eye. As part of stability testing, products were characterized via microbiological, physical, and chemical specifications parameters, including lidocaine hydrochloride monohydrate content for RHA Redensity® Eye Lido and mepivacaine hydrochloride content for RHA Redensity® Eye, and lidocaine-related or mepivacaine-related degradation products. Conformance of all batches with all specifications was confirmed up to the end of the studies. Therefore, RHA Redensity® Eye Lido and RHA Redensity® Eye dermal fillers have a 36-month and 24-month shelf life respectively with recommended storage conditions up to 25°C (77°F). ### X. SUMMARY OF PRIMARY CLINICAL STUDY The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness when injecting RHA Redensity® Eye Lido into the sub-dermis and supraperiosteum layers of the infraorbital region for the correction of moderate or severe infraorbital hollows in adults aged 22 years or over in the U.S. under IDE # G200191. Data from this clinical study was the basis for the PMA approval decision. Those data were leveraged for RHA Redensity® Eye as they are identical products with a different anesthetic agent. Clinical study IDE G190055 demonstrated the non-inferiority of mepivacaine to lidocaine in the device. A summary of the clinical study with RHA Redensity® Eye Lido is presented below. ### A. Study Design Patients were treated between December 2, 2020 and February 10, 2023. The database for this PMA reflected data collected through August 16, 2024 and included 248 subjects treated. There were 11 investigational sites. The study was a no-treatment control design with 183 subjects initially treated with RHA Redensity® Eye Lido and 65 subjects in the No-Treatment control group. After reaching the primary endpoint, the subjects in the No-Treatment control group were scheduled to receive treatment and followed the same study plan as those initially assigned to the treatment group. The study was a multicenter, blinded-evaluator, randomized, prospective, no-treatment control clinical investigation to identify whether RHA Redensity® Eye Lido was superior to no treatment for the correction of moderate to severe tissue volume deficiencies in the infraorbital regions. Subjects meeting inclusion/exclusion criteria were randomized 3:1 ratio into the treatment or control group. Patients receiving RHA Redensity® Eye Lido were further divided by the method of administration: injection with a needle (30G ½") or a cannula (25G 1 ½"). There was an approximate 1:1 distribution between the subgroups. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 6 {6} The primary effectiveness endpoint using the Teoxane Infra-orbital Hollows Scale (TIOHS) was evaluated at 12 weeks after Visit 1. All patients were followed for 52 weeks after injection to evaluate the long-term safety and effectiveness of RHA Redensity® Eye Lido when injected into the infraorbital regions. Safety and effectiveness assessments were also evaluated for 12 weeks after retreatment. The maximum volume of administration of RHA Redensity® Eye Lido was 1 mL per eye and per treatment. The study duration was nearly 18 months and included repeat treatment. # 1. Key Clinical Inclusion and Exclusion Criteria Enrollment in the pivotal study was limited to subjects who met the following inclusion criteria: - Outpatient, male or female of any race, 22 years of age or older. Female patients of childbearing potential must have had a negative urine pregnancy test (UPT) at Visit 1 and practice a reliable method of contraception throughout the study: - Had infraorbital volume loss of grades 2 to 3 on the Teoxane Infra-orbital Hollows Scale (TIOHS) for both eyes (ranging from 0 = none to 4 = very severe). Bilateral symmetry was not required. The blinded live evaluator (BLE) and treating investigator (TI) must independently assess and agree that this criterion was met; however, concordance of fullness was not required. If the assessments of the TI and the BLE were the same or differ by exactly 1 point on the scale, this difference was considered acceptable. The BLE assessment was used for the Baseline for the primary endpoint. - Was willing to abstain from facial aesthetic procedures/therapies that could interfere with study evaluations (e.g., other fillers, botulinum toxin injections, laser, or chemical resurfacing, facial plastic surgery) for the duration of the study Patients were not permitted to enroll in the study if they met any of the following exclusion criteria: - Had either one of the following assessments during the vision tests: Snellen acuity test worse than 20/40 (with corrections, if applicable); abnormal confrontational visual field test; or abnormal ocular motility test - Had known hypersensitivity or previous allergic reaction to any component of the study or the control device PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 7 {7} - Had known sensitivity to local anesthetics of the amide type, including known or suspected lidocaine hypersensitivity, history of multiple severe allergies, or history of anaphylactic shock - Compromised immunity, including but not limited to, poorly controlled diabetes mellitus (all types), autoimmune disease, or treatment with systemic corticosteroids, standard immunosuppressants, or biologics that may increase the risk of injection as judged by the TI. - Was planning to undergo during the study or had undergone any type of facial, plastic, nonablative, or reconstructive surgery (e.g. blepharoplasty, face lift, or rhinoplasty) within 6 months before randomization. Subject was also excluded if residual swelling is present or complete healing has not occurred within at least 6 months of the treatment received. - Had previously undergone or was planning to undergo prohibited treatment/procedures during certain time periods in the treated area or upper part of the face (above the lower orbital rim). ○ Semi-permanent dermal filler (e.g., calcium hydroxylapatite, poly-L-lactic acid) ≤24 months before randomization ○ Bioresorbable facial dermal filler (hyaluronic acid, collagen, or autologous fat) ≤ 12 months before randomization ○ Botulinum toxin injection ≤ 6 months before randomization ○ Permanent filler injection (e.g., polymethylmethacrylate, silicone) at any time in the past - Had prior lower eyelid surgery, including orbital or midface surgery, or has a permanent implant or graft in the midfacial region that could interfere with effectiveness assessments or plans to have it during the study - Had an orbital fat prolapse that might be linked to high weight variability (loos or gain), excessive lower eyelid skin laxity, ectropion, entropion, or previously/currently treated with fat injections ≤12 months before randomization - Had triangular malar mounds or fluid bags - Had ongoing cutaneous injection at the site of injection at randomization - Had known susceptibility to keloid formation, hypertrophic scarring, or clinically significant skin pigmentation disorders as judged by the TI - Had a history of connective tissue disease (rheumatoid arthritis, scleroderma, systemic lupus erythematosus) - Had a need for clinically significant, as judged by the TI, and continuous medical treatment within 2 weeks prior to Visit 1 PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 8 {8} - Had any significant concomitant skin disease or ocular condition that may interfere with the study assessment as judged by the TI. - Had known prolonged bleeding times because of disease or anticoagulant medication (including warfarin or low-dose aspirin). If food supplements with potential anticoagulant or antiplatelet effect (e.g., fish oil, omega-3, vitamin E, herbal supplements with garlic, or gingko biloba) were taken, the subject must have stopped them and waited 1 week or until bleeding times returned to normal before injecting. Supplements should not have been used for 1 week after the injection - Has eye tattoos, scars, lumps, or severe asymmetry that would interfere with visualization of the eye region for the effectiveness assessments as per TI discretion. - Had received any investigational product within 90 days prior to Visit 1 or planned to participate in another investigation during the course of the study - Had 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, as judged by the TI - Had clinically significant alcohol or drug abuse, or history of poor cooperation or unreliability, as judged by the TI - Was study staff or a close relative to study staff (e.g., parents, children, siblings, or spouse). # 2. Follow-up Schedule All patients were scheduled to return for follow-up examination at 2, 4, 8 and 12 weeks after the initial visit. Patients in the No-Treatment control group then crossed over and received injection and returned for follow-up examination at 2, 4, 8 and 12 weeks after their injection. All patients continued the study and returned for follow-up examinations at 24, 36 and 52 weeks after their injection. At which time, all patients were offered retreatment or exited the study. If patients received retreatment, they were scheduled to return for follow-up examinations at 2, 4 and 12 weeks after retreatment before exiting the study. All site visit windows were ±3 days except the visits at 24, 36 weeks after treatment and the visit 12 weeks after retreatment which were ±7 days. Pre-injection, patients performed visual assessments (Snellen visual acuity, confrontational visual field test and ocular motility test) and blink and PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 9 {9} closure tests. The TI and the BLE assessed the TIOHS grade of each eye and the patient completed *the Appraisal of lower eyelid* domain of the validated FACE-Q® patient-reported outcome measurement and part A of the Periorbital Subject Assessment Questionnaire (PSAQ) at Baseline. Postinjection and at every visit, the objective parameters measured during the study included: TIOHS and GAIS assessments by the TI; FACE-Q, GAIS, PSAQ and subject satisfaction assessments by the patient; TIOHS and GAIS assessments by the BLE starting at the primary endpoint and thereafter. Adverse events and complications were recorded at all visits. The key timepoints are shown below in Table 3 and Table 4 summarizing safety and effectiveness. **Table 3: Treatment Schedule** | | Treatment group RHA Redensity® Eye Lido | | No-Treatment group up to primary endpoint | | No-Treatment group After primary endpoint^{(2)} | | | --- | --- | --- | --- | --- | --- | --- | | Phase 1 | V1 – Visit 1 – Initial injection | Phase 1a | V1 | Phase 1a | V1b | Phase 1b | | | V2 – Visit 2 – 2 weeks | | V2 | | V2b | | | | V3 – Visit 3 – 4 weeks | | V3 | | V3b | | | | V4 – Visit 4 – 8 weeks | | V4 | | V4b | | | | V5 – Visit 5 – 12 weeks Primary endpoint | | V5 | | V5b | | | Phase 2 | V6 – Visit 6 – 24 weeks | | N/A | | V6 | | | | V7 – Visit 7 – 36 weeks | | | | V7 | | | | V8 – Visit 8 – 52 weeks^{1} Exit visit or retreatment | | | | V8 | | | | V9 – Visit 9 – 2 weeks after retreatment | | | | V9 | | | | V10 – Visit 10 – 4 weeks after retreatment | | | | V10 | | | | V11 – Visit 11 – 12 weeks after retreatment Exit visit | | | | V11 | | $^{(1)}$ Retreatment offered to all subjects $^{(2)}$ No-Treatment group received treatment after the first 12 weeks of their participation in the study and followed the same schedule as the Treatment group. V1/V1b means that the population of the Treatment group and the No-Treatment group after they had received treatment was pooled. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 10 {10} **Table 4: Treatment Schedule and Assessments** | | RHA Redensity® Eye Lido (Tx) / No-Treatment (No-Tx) | | Safety Assessments | Effectiveness Assessments | | | --- | --- | --- | --- | --- | --- | | | | Phase 1a Tx group No-Tx group | | | Phase 1b No-Treatment group only | | Initial treatment | V1/V1b | 0 weeks Initial treatment for Tx group only | 12 weeks after V1 Initial treatment | AEs If received Tx: Tyndall effect Blink / closure test Visual assessments CTR diary Pain VAS after injection | BLE: TIOHS TI: TIOHS Patient: FACE-Q, PSAQ (part A only) | | | V1call/ V1b call | 3 days after tx – phone call Tx group only | 3 days after tx – phone call | AEs CTR diary | N/A | | | V2 | 2 weeks | 2 weeks after tx | AEs If received Tx: Tyndall effect Blink / closure test Visual assessments CTR diary | TI: TIOHS | | | V3 | 4 weeks | 4 weeks after tx | AEs If received Tx: Tyndall effect Blink / closure test Visual assessments CTR diary | TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | | | V4 | 8 weeks | 8 weeks after tx | AEs If received Tx: Tyndall effect Blink / closure test Visual assessments | TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | | Phase 1a: Primary endpoint | V5 | **12 weeks** | 12 weeks after tx | AEs If received Tx: Tyndall effect Blink / closure test Visual assessments | BLE: TIOHS, GAIS TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | | **Phase 2** | | | | | | | | V6 | 24 weeks after tx | | AEs Tyndall effect Blink / closure test Visual assessments | BLE: TIOHS, GAIS TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | | | V7 | 36 weeks after tx | | AEs Tyndall effect Blink / closure test Visual assessments | BLE: TIOHS, GAIS TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 11 {11} | | RHA Redensity® Eye Lido (Tx) / No-Treatment (No-Tx) | | Safety Assessments | Effectiveness Assessments | | | --- | --- | --- | --- | --- | --- | | | | Phase 1a Tx group No-Tx group | | | Phase 1b No-Treatment group only | | Retreatment Or exit visit | V8 | 52 weeks after tx | | AEs Tyndall effect Blink / closure test Visual assessments If re-Tx: before and after visual assessments CTR diary Pain VAS after injection | BLE: TIOHS, GAIS TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | | | V8Call | 3 days after re-tx– phone call | | AEs CTR diary | N/A | | | V9 | 2 weeks after re-tx | | AEs Tyndall effect Blink / closure test Visual assessments CTR diary | BLE: TIOHS, GAIS TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | | | V10 | 4 weeks after re-tx | | AEs Tyndall effect Blink / closure test Visual assessments CTR diary | BLE: TIOHS, GAIS TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | | Exit visit | V11 | 12 weeks after re-tx | | AEs Tyndall effect Blink / closure test Visual assessments | BLE: TIOHS, GAIS TI: TIOHS, GAIS Patient: FACE-Q, GAIS, PSAQ, Subject satisfaction | Abbreviations: AE: Adverse Event; BLE: Blinded Live Evaluator; CTR: Common Treatment Response (30-day diary); GAIS: Global Aesthetic Improvement Scale; TI: Treatment Investigator; PSAQ: Periorbital Subjects Assessment Questionnaire; TIOHS: Teoxane Infraorbital Hollows Scale; Tx: Treatment; re-Tx: retreatment; VAS: Visual Analog Scale; Face-Q questionnaire used in the study: Appraisal of Lower Eyelids ### 3. Clinical Endpoints With regards to safety, patients reported injection site pain, completed visual assessments, blink and closure tests and reported their symptoms on a 30-Day patient Common Treatment Response (CTR) diary (after each injection). The TI assessed and reported all Adverse Events. The TI assessed all AEs and recorded details of seriousness, severity, duration, and action taken with study device, as well as relationship to the study device. For statistical analysis, the maximal severity reported for the AE was used, even if the AE presented as being less severe at some point during the event. With regards to effectiveness the infraorbital hollows improvement was assessed based on the validated Teoxane Infra-orbital Hollows Scale PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 12 {12} (TIOHS$^{1}$) (Table 5) by BLE and the TI. In addition to the TIOHS assessments, the BLE and the TI also assessed the patient using the GAIS (Global Aesthetic Improvement Scale). With regards to effectiveness from a patient’s perspective, the patient completed the following assessments: GAIS, FACE-Q Appraisal of Lower Eyelids, Periorbital Subject Assessment Questionnaire (PSAQ) and Subject Satisfaction questionnaire. **Table 5: Teoxane Infra-Orbital Hollows Scale (TIOHS)** | Category | Grade | Description | | --- | --- | --- | | None | 0 | No visible infraorbital hollowing. Absence of medial and lateral volume loss in this area. Smooth lid-cheek junctions | | Minimal | 1 | Mild infraorbital hollowing with limited loss of volume medial to the mid-pupillary line. Smooth lid-cheek junction | | Moderate | 2 | Moderate infraorbital hollowing extending laterally beyond the mid-pupillary line with moderate loss of volume in at least ¼ of the lower orbital rim. Some volume loss will be present at the lid-cheek junction. May have volume deficiency in the medial cheek with flattening of the central upper cheek. | | Severe | 3 | Severe infraorbital hollowing with moderate volume loss in the entire lower orbital rim. Full depression following creating a deeply defined groove at the lid-cheek junction. | | Very Severe | 4 | Very severe infraorbital hollowing with severe loss of volume along the entire lower orbital rim. A very marked groove will be present along the lid-cheek junction. | With regard to success/failure criteria, the effectiveness of RHA Redensity$^{®}$ Eye Lido would be demonstrated if 1) the TIOHS responder rate of subjects treated with RHA Redensity$^{®}$ Eye Lido was statistically superior to the responder rate for subjects of the No-Treatment group 12 weeks after randomization as assessed by the BLE; and 2) the mean change from Baseline of the modified FACE-Q *Appraisal of lower eyelids* of subjects treated with RHA Redensity$^{®}$ Eye Lido was statistically superior to the raw score for subjects of the No-Treatment group 12 weeks after randomization as assessed by the subject. $^{1}$ Carey W., Trévidic P., Benedetto A., Maffert P. and Antunes S. - *Creation and Validation of Photonumeric Scale for Assessment of Infraorbital Hollows* – Dermatologic Surgery – August 2023 – Volume 49 – Number 8 –777:782. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 13 {13} # **B. Accountability of PMA Cohort** At the time of the database lock, of the 248 patients enrolled in the PMA study, 83% (205/248) were followed for 52 weeks following their treatment before being offered retreatment. 95 of them (38%) exited the study at this visit and 110 received retreatment and continued the follow-up. 108 patients (44%) were available for analysis at the final visit, 12 weeks after retreatment. Overall, 203 of the 248 patients (82%) completed the study. A total of 281 subjects were screened and 248 were enrolled. Out of these enrolled subjects: - 248 subjects (100%) were assigned to the Safety Population (SAFT) - 248 subjects (100%) to the intent-to-treat (ITT) population - 218 subjects (87.9%) to the per protocol (PP) population (16 subjects (8.7%) in RHA Redensity® Eye Lido group and 14 subjects (21.5%) in No-Treatment control group). The PP population are all subjects in the ITT who completed up to Visit 5 (primary endpoint visit at 12 weeks) with no major protocol deviation that could affect effectiveness assessment). Of the 30 subjects (5.2%) who were excluded from the PP: - 13 had a major protocol deviation: 6 (2.4%) subjects had their Visit 5 visit out of windows, 5 (2.0%) subjects missed Visit 5, and 2 (0.8%) subjects did not meet the inclusion criteria. - 17 subjects discontinued the study before Visit 5: 5 (2.0%) in the RHA Redensity® Eye Lido treatment group and 12 (4.8%) in the No-Treatment control group For the pooled population, of the 65 subjects in the No-Treatment group, 13 did not reach Visit 5 to crossover and receive RHA Redensity® Eye Lido treatment and 2 of the 50 who reached Visit 5 did not receive treatment at that visit. Therefore, there were 233 subjects as part of the safety population (SAFT) for the pooled data set. The overall Safety population includes all subjects who were assigned to the treatment or No-Treatment control groups and completed Visit 1. The Safety population of the pooled data set consists of all subjects who received at least one treatment with the study device. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 14 {14}  **Figure 1: Subject Population** **Table 6: Subject Accountability and Disposition (ITT population)** | | RHA Redensity® Eye Lido | No-Treatment control | | --- | --- | --- | | Screened | 281 | | | Enrolled | 248 | | | Safety population | 183 | 65 | | ITT population | 183 | 65 | | PP population | 167 | 51 | | Number of subjects who completed the study | 160 (87.4%) | 43 (66.2%) | | Number of subjects at primary endpoint visit (V5 – 12 weeks) | 173 (94.5%) | 52 (80.0%) | | Number of subjects at V8 (52 weeks) | 160 (87.4%) | 45 (69.2%) | | Number of subjects who received retreatment at V8 | 88 (48.1%) | 22 (33.8%) | | Number of subjects withdrawn from study | 23 (12.6%) | 22 (33.8%) | | Reason for discontinuation | | | | *A subject or legal representative withdrawal* | 11 (6.0%) | 12 (18.5%) | | *Investigator withdrawal* | 2 (1.1%) | 1 (1.5%) | | *Lost to follow-up* | 7 (3.8%) | 6 (9.2%) | | *Sponsor decision* | 1 (0.5%) | 0 (0%) | | *Other* | 2 (1.1%) | 3 (4.6%) | All percentages are based on the number of subjects by group in the ITT population. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 15 {15} ### C. Study Population Demographics and Baseline Parameters #### a) Demographics The demographics of the study population were typical for a pivotal study performed in the United States. The study population included female and male subjects who were $\geq 22$ years old. The study ensured that subjects meeting the inclusion criteria were representative of gender and ethnicity of the U.S. population who may use RHA Redensity® Eye Lido implant for the treatment of infraorbital region. Subjects had a mean age of approximately 50 years, and most subjects were female (approximately 88.7% (220/248) of study subjects). The majority of subjects were white (84.7% - 210/248), with 8.9% (22/248) of subjects identifying as Black or African American. 25.8% (64/248) of subjects were of Hispanic or Latino ethnicity. Fitzpatrick Skin Types were appropriately represented with all predefined minimal sample size thresholds being attained for subjects with skin types IV-VI, with approximately 66.1% (164/248) and 33.9% (84/248) of subjects had skin types I-III and IV-VI, respectively (and 7.6% (19/248) of subjects having skin types V/VI). **Table 7: Demographic Characteristics at Baseline (ITT population)** | Variable | Sample Characteristics / Category | RHA Redensity® Eye Lido (N = 183) | No-Treatment (N = 65) | Total (N = 248) | | --- | --- | --- | --- | --- | | Age [years] | n (missing) | 183 (0) | 65 (0) | 248 (0) | | Mean (SD) | 50.0 (10.65) | 48.2 (11.11) | 49.5 (10.78) | | Median | 51.0 | 49.0 | 51.0 | | Min to Max | 24 to 73 | 23 to 73 | 23 to 73 | | 22 – ≤ 51^{(a)} | 92 (50.3%) | 38 (58.5%) | 130 (52.4%) | | > 51^{(a)} | 91 (49.7%) | 27 (41.5%) | 118 (47.6%) | | Sex | n (missing) | 183 (0) | 65 (0) | 248 (0) | | Male | 23 (12.6%) | 5 (7.7%) | 28 (11.3%) | | Female | 160 (87.4%) | 60 (92.3%) | 220 (88.7%) | | Ethnicity | n (missing) | 183 (0) | 65 (0) | 248 (0) | | Hispanic or Latino | 49 (26.8%) | 15 (23.1%) | 64 (25.8%) | | Not Hispanic or Latino | 130 (71.0%) | 49 (75.4%) | 179 (72.2%) | | Not available | 4 (2.2%) | 1 (1.5%) | 5 (2.0%) | | Race^{[2]} | n (missing) | 183 (0) | 65 (0) | 248 (0) | | Not allowed by local law/Unknown | 4 (2.2%) | 1 (1.5%) | 5 (2.0%) | | American Indian or Alaska Native | 2 (1.1%) | 1 (1.5%) | 3 (1.2%) | | Asian | 6 (3.3%) | 0 | 6 (2.4%) | | Black or African American | 17 (9.3%) | 5 (7.7%) | 22 (8.9%) | | Native Hawaiian or Other Pacific Islander | 3 (1.6%) | 0 | 3 (1.2%) | | White | 152 (83.1%) | 58 (89.2%) | 210 (84.7%) | PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 16 {16} | Variable | Sample Characteristics / Category | RHA Redensity® Eye Lido (N = 183) | No-Treatment (N = 65) | Total (N = 248) | | --- | --- | --- | --- | --- | | Fitzpatrick Skin | n (missing) | 183 (0) | 65 (0) | 248 (0) | | Type | I-III | 121 (66.1%) | 43 (66.2%) | 164 (66.1%) | | IV-VI | 62 (33.9%) | 22 (33.8%) | 84 (33.9%) | | V-VI | 14 (7.7%) | 5 (7.7%) | 19 (7.6%) | Abbreviations: N = number of subjects; SD = standard deviation All percentages are based on the number of subjects by group with non-missing information for each variable. (a) 51 corresponds to the median age of the total ITT population. [1] For female, being not of childbearing potential is defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy). [2] A subject can be counted in several categories. ### b) **Extent of exposure** The number of treatment sessions is described in Table 8 below. All subjects who received retreatment were injected with RHA Redensity® Eye Lido. **Table 8: Number of Treatment Sessions – Safety Population** | Treatment | RHA Redensity® Eye Lido Needle (N=116) | RHA Redensity® Eye Lido Cannula (N=117) | RHA Redensity® Eye Lido Total (N=233) | | --- | --- | --- | --- | | Initial treatment | 116 (100%) | 117 (100%) | 233 (100%) | | Retreatment | 48 (41.4%) | 62 (53.0%) | 110 (47.2%) | | Number of subjects receiving 1 treatment (i.e., only initial treatment) | 68 (58.6%) | 55 (47.0%) | 123 (52.8%) | | Number of subjects receiving 2 injections (initial and retreatment) | 48 (41.4%) | 62 (53.0%) | 110 (47.2%) | All percentages are based on the number of subjects by group in the population. For each individual subject, the method of administration was the same at initial and retreatment. Method of administration was a 1:1 ratio between needle and cannula with 116 subjects injected with a needle and 117 subjects injected with a cannula. Among the SAFT population (248 subjects), 233 subjects received an initial treatment with RHA Redensity® Eye Lido (94.0%, 233/248) and of those, 110 subjects received a retreatment at 52 weeks after their initial treatment (47.2%, 110/233). The mean (SD) volume injected for both eyes after initial treatment was 1.52 (0.526) mL. The mean volume injected at retreatment was lower, it was 0.91 mL (0.472) on average. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 17 {17} # **c) Administration method and depth of injection** The majority of subjects (83.6%, 97/116) who received needle injections were administered into the supraperiosteum. Additionally, 14.6% (17/116) were injected both into the sub-dermis and supraperiosteum layers. Only 1.7% (2/116) were injected solely into the sub-dermis. The distribution was more balanced for subjects injected with a cannula. The majority of subjects injected with a cannula were injected into both the sub-dermis and supraperiosteum (53.0%, 62/117) and the rest was relatively balanced into the other 2 categories: 28.2% (33/117) of subjects injected into the sub-dermis only and 18.8% (22/117) of subjects injected into the supraperiosteum only. **Table 9: Method of Injection and Injection Depth – Safety Population** | Treatment | | Needle (N=116) | Cannula (N=117) | Total (N=233) | | --- | --- | --- | --- | --- | | **Initial treatment** Depth | # of subject injected | 116 | 117 | 233 | | | Sub-dermis | 2 (1.7%) | 33 (28.2%) | 35 (15.0%) | | | Supraperiosteum | 97 (83.6%) | 22 (18.8%) | 119 (51.1%) | | | Both | 17 (14.7%) | 62 (53.0%) | 79 (33.9%) | | Technique | Anterograde linear threading | 12 (10.3%) | 4 (3.4%) | 16 (6.9%) | | | Retrograde linear threading | 4 (3.4%) | 91 (77.8%) | 95 (40.8%) | | | Multipuncture technique | 96 (82.8%) | 0 | 96 (41.2%) | | | Other | 4 (3.4%) | 22 (18.8%) | 26 (11.2%) | | **Retreatment** Depth | # of subject injected | 48 | 62 | 110 | | | Sub-dermis | 4 (8.3%) | 18 (29.0%) | 22 (20.0%) | | | Supraperiosteum | 35 (72.9%) | 20 (32.3%) | 55 (50.0%) | | | Both | 9 (18.8%) | 24 (38.7%) | 33 (30.0%) | | Technique | Anterograde linear threading | 4 (8.3%) | 3 (4.8%) | 7 (6.4%) | | | Retrograde linear threading | 1 (2.1%) | 46 (74.2%) | 47 (42.7%) | | | Multipuncture technique | 36 (75.0%) | 0 | 36 (32.7%) | | | Other | 7 (14.6%) | 13 (21.0%) | 20 (18.2%) | # **D. Safety and Effectiveness Results** # **1. Safety Results** The analysis of safety was based on the Safety pooled population (i.e., population from the Treatment group + population of the No-Treatment group after their received treatment after the primary endpoint). It is based on a cohort of 233 subjects available for up to 52 weeks after initial treatment. The common treatment responses for this study are presented below in Table 10 to Table 12. Adverse device effects are reported in Table 13 to Table 16. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 18 {18} Safety of the RHA Redensity® Eye Lido implant when injected into the infraorbital region was evaluated through a 30-Day patient Common Treatment Response (CTR) diary which was completed after each injection, AE assessments at each visit, visual assessment at each visit and measurement of injection site pain. **a) Common Treatment Responses after initial treatment** CTR data for initial treatment are presented in Table 10 for the needle and cannula subgroups. CTRs for retreatment were of the same proportions. After initial injection at Visit 1/1b was administered to 233 subjects, 223 CTR diaries were retrieved, and 181 subjects experienced at least 1 CTR (181/223 [81.2%]). The incidence of subjects experiencing at least 1 CTR was slightly higher in the needle subgroup (89.1%, 98/110) than in the cannula subgroup (73.5%, 83/113). Overall, the most common CTR after the initial injection at Visit 1/1b was “tenderness” in 57.4% of subjects (128/223), followed by “swelling” in 57.0% of subjects (127/223), “bruising” in 54.7% of subjects (122/223), “lumps/bumps” in 49.3% of subjects (110/223), “firmness” in 44.4% of subjects (99/223), “redness” in 35.9% of subjects (80/223), “discoloration” in 35.9% of subjects (80/223), “pain” in 18.8% of subjects (42/223), and “itching” in 11.2% of subjects (25/223) was the least frequent. After the initial injection at Visit 1/1b, the maximum severity of CTRs reported by the subjects in their diaries were distributed as follows: - None: 18.8% (42/223) of subjects did not experience any CTRs - Mild: 51.1% (114/223) of subjects experienced mild CTRs as maximum severity - Moderate: 25.6% (57/223) of subjects experienced moderate CTRs as maximum severity - Severe: 4.5% (10/223) of subjects experienced severe CTRs as maximum severity Most severe CTRs were reported when injected with a needle (9 of the 10 severe CTRs) and the most frequent severe CTRs reported was bruising which is consistent and anticipated when injecting with a needle compared to a cannula. 69.1% of subjects (154/223) experienced a CTR that lasted 1-3 days and 25.6% of subjects (57/223) experienced CTRs that lasted between 15 and 30 days. The incidence rates by number of days were similar between needle PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 19 {19} and cannula subgroups following the initial injection. Of the 813 CTRs, 70.2% (576/813) had resolved by day 7. By the end of the diary, nearly all CTRs had resolved (95.7% [807/843]). On the last day of the diary, 12.1% (27/223) of subjects were experiencing a CTR. The most frequent CTR was lumps/bumps (33.3% [12/36]). All CTRs on the last day of the diary were automatically elevated to an Adverse Event and their severity assessed by the TI and all were assessed as “mild”. **Table 10: CTRs Incidence Rate – Initial Treatment (V1/V1b) – Safety Population** | CTR | Needle | Cannula | Total | | --- | --- | --- | --- | | Number of subjects | 116 | | 117 | | Number of CTR diaries retrieved | 110 | | 113 | | ≥1 CTR | 98 (89.1%) | [81.9- 93.6%] | 83 (73.5%) | | Redness | 54 (49.1%) | [39.9- 58.3%] | 26 (23.0%) | | Pain | 21 (19.1%) | [12.8- 27.4%] | 21 (18.6%) | | Tenderness | 60 (54.5%) | [45.2- 63.5%] | 68 (60.2%) | | Firmness | 51 (46.4%) | [37.3- 55.6%] | 48 (42.5%) | | Swelling | 73 (66.4%) | [57.1- 74.5%] | 54 (47.8%) | | Lumps/Bumps | 60 (54.5%) | [45.2- 63.5%] | 50 (44.2%) | | Bruising | 79 (71.8%) | [62.8- 79.4%] | 43 (38.1%) | | Itching | 15 (13.6%) | [8.4- 21.3%] | 10 (8.8%) | | Discoloration | 48 (43.6%) | [34.7- 53.0%] | 32 (28.3%) | Abbreviation: CTR = Common Treatment Response. All percentages are based on the number of CTR diaries retrieved by injection by subgroup in the population. **Table 11: CTRs by Maximum Severity – Initial Treatment (V1/V1b) – Safety Population** | CTR | Severity | Needle | Cannula | Total | | --- | --- | --- | --- | --- | | Number of subjects | | 116 | 117 | 233 | | Number of CTR diaries retrieved | | | 110 | 113 | | At least 1 CTR | None | 12 (10.9%) | 30 (26.5%) | 42 (18.8%) | | | Mild | 50 (45.5%) | 64 (56.6%) | 114 (51.1%) | | | Moderate | 39 (35.5%) | 18 (15.9%) | 57 (25.6%) | | | Severe | 9 (8.2%) | 1 (0.9%) | 10 (4.5%) | | Redness | None | 56 (50.9%) | 87 (77.0%) | 143 (64.1%) | | | Mild | 41 (37.3%) | 23 (20.4%) | 64 (28.7%) | | | Moderate | 10 (9.1%) | 3 (2.7%) | 13 (5.8%) | | | Severe | 3 (2.7%) | 0 | 3 (1.3%) | | Pain | None | 89 (80.9%) | 92 (81.4%) | 181 (81.2%) | | | Mild | 19 (17.3%) | 20 (17.7%) | 39 (17.5%) | | | Moderate | 2 (1.8%) | 1 (0.9%) | 3 (1.3%) | | | Severe | 0 | 0 | 0 | PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 20 {20} | CTR | Severity | Needle | Cannula | Total | | --- | --- | --- | --- | --- | | Tenderness | None | 50 (45.5%) | 45 (39.8%) | 95 (42.6%) | | | Mild | 54 (49.1%) | 59 (52.2%) | 113 (50.7%) | | | Moderate | 6 (5.5%) | 9 (8.0%) | 15 (6.7%) | | | Severe | 0 | 0 | 0 | | Firmness | None | 59 (53.6%) | 65 (57.5%) | 124 (55.6%) | | | Mild | 36 (32.7%) | 44 (38.9%) | 80 (35.9%) | | | Moderate | 14 (12.7%) | 4 (3.5%) | 18 (8.1%) | | | Severe | 1 (0.9%) | 0 | 1 (0.4%) | | Swelling | None | 37 (33.6%) | 59 (52.2%) | 96 (43.0%) | | | Mild | 48 (43.6%) | 45 (39.8%) | 93 (41.7%) | | | Moderate | 22 (20.0%) | 9 (8.0%) | 31 (13.9%) | | | Severe | 3 (2.7%) | 0 | 3 (1.3%) | | Lumps/Bumps | None | 50 (45.5%) | 63 (55.8%) | 113 (50.7%) | | | Mild | 40 (36.4%) | 43 (38.1%) | 83 (37.2%) | | | Moderate | 18 (16.4%) | 6 (5.3%) | 24 (10.8%) | | | Severe | 2 (1.8%) | 1 (0.9%) | 3 (1.3%) | | Bruising | None | 31 (28.2%) | 70 (61.9%) | 101 (45.3%) | | | Mild | 45 (40.9%) | 37 (32.7%) | 82 (36.8%) | | | Moderate | 28 (25.5%) | 6 (5.3%) | 34 (15.2%) | | | Severe | 6 (5.5%) | 0 | 6 (2.7%) | | Itching | None | 95 (86.4%) | 103 (91.2%) | 198 (88.8%) | | | Mild | 14 (12.7%) | 9 (8.0%) | 23 (10.3%) | | | Moderate | 1 (0.9%) | 1 (0.9%) | 2 (0.9%) | | | Severe | 0 | 0 | 0 | | Discoloration | None | 62 (56.4%) | 81 (71.7%) | 143 (64.1%) | | | Mild | 31 (28.2%) | 29 (25.7%) | 60 (26.9%) | | | Moderate | 14 (12.7%) | 3 (2.7%) | 17 (7.6%) | | | Severe | 3 (2.7%) | 0 | 3 (1.3%) | Abbreviation: CTR = Common Treatment Response. All percentages are based on the number of subjects with the specific CTR by injection by subgroup in the population. Maximum severity (Severe>Moderate>Mild) reported by the subject for the particular CTR in the diary for at least one day. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 21 {21} **Table 12: CTRs by Total Duration – Initial Treatment (V1/V1b)– Safety Population** | Total Duration (days) | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | CTR after initial injection | Group | Subjects Experiencing the CTR | 1-3 | 4-7 | 8-14 | 15-30 | Last Day Diary | | Any CTR | Needle | 98 (89.1%) | 81 (73.6%) | 67 (60.9%) | 46 (41.8%) | 43 (39.1%) | 13 (11.8%) | | | Cannula | 83 (73.5%) | 70 (61.9%) | 42 (37.2%) | 22 (19.5%) | 23 (20.4%) | 14 (12.4%) | | | Total | 181 (81.2%) | 151 (67.7%) | 109 (48.9%) | 68 (30.5%) | 66 (29.6%) | 27 (12.1%) | | Redness | Needle | 54 (49.1%) | 35 (31.8%) | 13 (11.8%) | 2 (1.8%) | 4 (3.6%) | 2 (1.8%) | | | Cannula | 26 (23.0%) | 19 (16.8%) | 3 (2.7%) | 1 (0.9%) | 3 (2.7%) | 0 | | | Total | 80 (35.9%) | 54 (24.2%) | 16 (7.2%) | 3 (1.3%) | 7 (3.1%) | 2 (0.9%) | | Pain | Needle | 21 (19.1%) | 15 (13.6%) | 4 (3.6%) | 2 (1.8%) | 0 | 0 | | | Cannula | 21 (18.6%) | 18 (15.9%) | 1 (0.9%) | 1 (0.9%) | 1 (0.9%) | 0 | | | Total | 42 (18.8%) | 33 (14.8%) | 5 (2.2%) | 3 (1.3%) | 1 (0.4%) | 0 | | Tenderness | Needle | 60 (54.5%) | 29 (26.4%) | 21 (19.1%) | 7 (6.4%) | 3 (2.7%) | 0 | | | Cannula | 68 (60.2%) | 40 (35.4%) | 14 (12.4%) | 7 (6.2%) | 7 (6.2%) | 2 (1.8%) | | | Total | 128 (57.4%) | 69 (30.9%) | 35 (15.7%) | 14 (6.3%) | 10 (4.5%) | 2 (0.9%) | | Firmness | Needle | 51 (46.4%) | 19 (17.3%) | 15 (13.6%) | 8 (7.3%) | 9 (8.2%) | 0 | | | Cannula | 48 (42.5%) | 29 (25.7%) | 12 (10.6%) | 4 (3.5%) | 3 (2.7%) | 2 (1.8%) | | | Total | 99 (44.4%) | 48 (21.5%) | 27 (12.1%) | 12 (5.4%) | 12 (5.4%) | 2 (0.9%) | | Swelling | Needle | 73 (66.4%) | 26 (23.6%) | 17 (15.5%) | 17 (15.5%) | 13 (11.8%) | 4 (3.6%) | | | Cannula | 54 (47.8%) | 29 (25.7%) | 12 (10.6%) | 7 (6.2%) | 6 (5.3%) | 3 (2.7%) | | | Total | 127 (57.0%) | 55 (24.7%) | 29 (13.0%) | 24 (10.8%) | 19 (8.5%) | 7 (3.1%) | | Lumps/ Bumps | Needle | 60 (54.5%) | 23 (20.9%) | 14 (12.7%) | 12 (10.9%) | 11 (10.0%) | 5 (4.5%) | | | Cannula | 50 (44.2%) | 21 (18.6%) | 10 (8.8%) | 6 (5.3%) | 13 (11.5%) | 7 (6.2%) | | | Total | 110 (49.3%) | 44 (19.7%) | 24 (10.8%) | 18 (8.1%) | 24 (10.8%) | 12 (5.4%) | | Bruising | Needle | 79 (71.8%) | 6 (5.5%) | 32 (29.1%) | 22 (20.0%) | 19 (17.3%) | 2 (1.8%) | | | Cannula | 43 (38.1%) | 17 (15.0%) | 12 (10.6%) | 11 (9.7%) | 3 (2.7%) | 2 (1.8%) | | | Total | 122 (54.7%) | 23 (10.3%) | 44 (19.7%) | 33 (14.8%) | 22 (9.9%) | 4 (1.8%) | | Itching | Needle | 15 (13.6%) | 9 (8.2%) | 4 (3.6%) | 1 (0.9%) | 1 (0.9%) | 0 | | | Cannula | 10 (8.8%) | 7 (6.2%) | 2 (1.8%) | 0 | 1 (0.9%) | 0 | | | Total | 25 (11.2%) | 16 (7.2%) | 6 (2.7%) | 1 (0.4%) | 2 (0.9%) | 0 | | Discoloration | Needle | 48 (43.6%) | 14 (12.7%) | 12 (10.9%) | 10 (9.1%) | 12 (10.9%) | 4 (3.6%) | | | Cannula | 32 (28.3%) | 14 (12.4%) | 8 (7.1%) | 4 (3.5%) | 6 (5.3%) | 3 (2.7%) | | | Total | 80 (35.9%) | 28 (12.6%) | 20 (9.0%) | 14 (6.3%) | 18 (8.1%) | 7 (3.1%) | Abbreviation: CTR = Common Treatment Response. All percentages are based on the number of CTR diaries retrieved by injection by group in the population. 116 subjects were treated with a needle and 110 CTR diaries were retrieved. 117 subjects were treated with a cannula and 113 CTR diaries were retrieved. Total duration is defined as the number of days +1 between the first and last occurrence of the CTR in the diary, no matter if there was a gap between the several occurrences. The incidence rate of any CTR tended to be higher when injected with a needle (89%) than when injected with a cannula (73%). The CTR incidence PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 22 {22} rates by duration were similar between needle and cannula following initial treatment. 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 elevated to the level of an AE after 30 days, the TI determined that all the AEs were of “mild” intensity. **b) Adverse Device Effects that occurred in the PMA clinical study** All Adverse Device Effects (Table 13) were the types and frequency of adverse events that are typically experienced following the injection of a dermal filler into the infraorbital hollows. From Visit 1/1b to Visit 8 (i.e., not including retreatment injections), 57 ADEs were reported (Table 13): - 19.0% (22/116) subjects (28 events) in the needle group - 15.4% (18/117) subjects (29 events) in the cannula group Overall, most ADEs were obtained from the diary. Of the 57 ADEs reported from 40 subjects (17.2%, 40/233) after initial treatment: - 8.6% (40/233) of subjects experienced ADEs that were CTRs automatically elevated to AEs because they were present on the last day of the diary. - 3.4% (8/233) of subjects experienced ADEs that were automatically elevated to AEs because they were reported as “Other” in the diary. - 3.4% (8/233) of subjects experienced ADEs that were identified by the TI during a visit. - 2.1% (5/233) of subjects experienced ADEs that were reported from a pre-identified list of AEs in the subject diary but were not a CTR. Out of these 5 ADEs (in 5 subjects), none were related to visual disturbances (3 events of headache, 1 event of atypical migraine and 1 event of swelling in infraorbital area on the right side). All were mild except 1 event of headache reported as moderate. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 23 {23} **Table 13: Adverse Events Profile Overview (Initial, Touch-Up) Visit 1/1b to Visit 8 – Safety Population** | From V1 to V7 | Needle (N=116) | | Cannula (N=117) | | Total (N=233) | | | --- | --- | --- | --- | --- | --- | --- | | | Number of events | Number of subjects (%) | Number of events | Number of subjects (%) | Number of events | Number of subjects (%) | | **Overall** | | | | | | | | Number of subjects | | 116 | | 117 | | 233 | | All AEs | 34 | 26 (22.4%) [15.8-30.8%] | 58 | 36 (30.8%) [23.1-39.6%] | 92 | 62 (26.6%) [21.3-32.6%] | | AESIs | 0 | 0 | 4 | 3 (2.6%) [0.9-7.3%] | 4 | 3 (1.3%) [0.4-3.7%] | | ADEs | 28 | 22 (19.0%) [12.9-27.0%] | 29 | 18 (15.4%) [10.0-23.0%] | 57 | 40 (17.2%) [12.9-22.5%] | | UADEs | 0 | 0 | 0 | 0 | 0 | 0 | | Serious AEs | 0 | 0 | 1 | 1 (0.9%) [0.2-4.7%] | 1 | 1 (0.4%) [0.1-2.4%] | | Device-related Serious AEs | 0 | 0 | 0 | 0 | 0 | 0 | Abbreviations: ADE = adverse device effect; AE = adverse event; AESI = adverse event of special interest; N = number of subjects; SAE = serious adverse event; SAFT = safety (population); UADE = unanticipated adverse device effect Notes: Number (%) of subjects with at least 1 AE in the category. All percentages are based on the number of subjects by group in the population. An AESI is any new vision disturbances including, but not limited to, any loss of vision, blurriness, double vision, pain in or around the eye, blindness, blind spot or shadow in the visual field, trouble moving eyes, ocular hypotonia, ptosis, etc. that occurs after any administration of the filler. A related AE is an AE that was judged by the investigator to be Possibly Related or Probably Related or Causal relationship to study device or study procedure. AEs with a missing relationship were counted as Related. A device-related SAE is a related AE also considered serious. The type and rates of ADEs were also comparable between the needle and cannula groups as shown by Table 14. Similar safety profiles were observed between the needle and cannula groups: a total of 19.0% (22/117) and 15.4% (18/117) subjects in needle and cannula groups respectively, experienced at least 1 ADE between Visit 1/1b and Visit 8. The most common events were: - Injection site discoloration experienced by 5.2% (12/233) of subjects (14 events) - Injection site mass, experienced by 3.9% (9/233) of subjects (10 events) - Injection site swelling, experienced by 3.9% (9/233) of subjects (9 events) There were no noticeable differences of the frequencies of ADEs between the needle and cannula groups. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 24 {24} **Table 14: ADEs sorted by SOC and PT (Visit 1/1b to Visit 8 – Initial Treatment to 52 Weeks Follow-Up Excluding Retreatment – Pooled) – Safety Population** | From V1/V1b to V8 SOC PT | Needle (N=116) | | Cannula (N=117) | | Total (N=233) | | | --- | --- | --- | --- | --- | --- | --- | | | Number of events | Number of subjects | Number of events | Number of subjects | Number of events | Number of subjects | | **Any ADE** | **28** | **22 (19.0%)** | **29** | **18 (15.4%)** | **57** | **40 (17.2%)** | | **General Disorders and Admin. Site Conditions** | **24** | **19 (16.4%)** | **24** | **15 (12.8%)** | **48** | **34 (14.6%)** | | Injection Site Discolouration | 5 | 5 (4.3%) | 9 | 7 (6.0%) | 14 | 12 (5.2%) | | Injection Site Mass | 5 | 4 (3.4%) | 5 | 5 (4.3%) | 10 | 9 (3.9%) | | Injection Site Swelling | 5 | 5 (4.3%) | 4 | 4 (3.4%) | 9 | 9 (3.9%) | | Injection Site Bruising | 3 | 3 (2.6%) | 1 | 1 (0.9%) | 4 | 4 (1.7%) | | Injection Site Oedema | 2 | 2 (1.7%) | 0 | 0 | 2 | 2 (0.9%) | | Injection Site Pain | 0 | 0 | 2 | 2 (1.7%) | 2 | 2 (0.9%) | | Injection Site Reaction | 1 | 1 (0.9%) | 1 | 1 (0.9%) | 2 | 2 (0.9%) | | Injection Site Erythema | 1 | 1 (0.9%) | 0 | 0 | 1 | 1 (0.4%) | | Injection Site Haemorrhage | 0 | 0 | 1 | 1 (0.9%) | 1 | 1 (0.4%) | | Injection Site Induration | 0 | 0 | 1 | 1 (0.9%) | 1 | 1 (0.4%) | | Injection Site Scab | 1 | 1 (0.9%) | 0 | 0 | 1 | 1 (0.4%) | | Injection Site Urticaria | 1 | 1 (0.9%) | 0 | 0 | 1 | 1 (0.4%) | | **Nervous System Disorders** | **3** | **3 (2.6%)** | **2** | **2 (1.7%)** | **5** | **5 (2.1%)** | | Headache | 3 | 3 (2.6%) | 1 | 1 (0.9%) | 4 | 4 (1.7%) | | Atypical Migraine | 0 | 0 | 1 | 1 (0.9%) | 1 | 1 (0.4%) | | **Eye Disorders** | **0** | **0** | **2** | **1 (0.9%)** | **2** | **1 (0.4%)** | | Abnormal Sensation In Eye | 1 | 1 (0.9%) | 0 | 0 | 1 | 1 (0.4%) | | Asthenopia | 1 | 1 (0.9%) | 0 | 0 | 1 | 1 (0.4%) | | **Injury, Poisoning And Procedural Complications** | **0** | **0** | **1** | **1 (0.9%)** | **1** | **1 (0.4%)** | | Contusion | 0 | 0 | 1 | 1 (0.9%) | 1 | 1 (0.4%) | | **Skin And Subcutaneous Tissue Disorders** | **1** | **1 (0.9%)** | **0** | **0** | **1** | **1 (0.4%)** | | Erythema | 1 | 1 (0.9%) | 0 | 0 | 1 | 1 (0.4%) | Abbreviations: ADE = adverse device effect; MedDRA = Medical Dictionary for Regulatory Activities; N = number of subjects; PT = preferred term; SAFT = safety (population); SOC = system organ class; V = visit All percentages were based on the number of subjects by group in the population. ADEs were coded using MedDRA version 24.0. AEs are displayed by descending subject frequency of SOC, then descending subject frequency of PT within SOC in the Total column, then alphabetically. The majority (93.0%, 53/57) of ADEs were mild and the remaining were moderate (7.0%, 4/57) (Table 15). There were no severe ADEs. The rates were similar between the needle and cannula groups: 28 ADEs reported in the needle subgroup by 22/116 subjects [19.0%]; 29 ADEs reported in the cannula subgroup by 18/117 subjects [15.4%]. There were no severe ADEs reported. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 25 {25} Of the 57 events reported between Visit 1/1b and Visit 8, 24.6% (14/57) of ADEs lasted 1 to 3 days, 50.9% (29/57) ADEs lasted less than 14 days and 71.9% (41/57) were resolved in 30 days. ADEs tended to resolve faster in the needle subgroup with 67.9% (19/28) that lasted less than 14 days against 34.5% (10/29) in the cannula subgroup that lasted less than 14 days. The mean (SD) duration of ADEs was 34.1 (55.38) days for all the subjects treated, with 38.9 (41.15) days in the cannula subgroup, and 29.0 (67.47) days in the needle subgroup. A small proportion of ADEs lasted more than 90 days (5/57, 8.8%) with a similar proportion in the needle (2/28, 7.1%) and cannula (3/29, 10.3%) subgroups. Two (2) events in the needle subgroup and 3 events in the cannula subgroup, recorded for 5 subjects, lasted more than 90 days. Of these 5 ADEs, the longest duration was 264 days, recorded for a persistent edema of mild severity that resolved without sequelae. This was followed by an event lasting 261 days, a worsening of left eye festoon of mild severity, which also resolved without sequelae. Three additional ADEs had durations ranging from 97 to 155 days: “bilateral periorbital puffiness” (155 days), “Tyndall effect” (148 days), and “left lateral IOH region visible filler product” (97 days), all of mild severity and which resolved without sequelae. Almost all ADEs resolved by exit, except 3 ongoing events related to 2 subjects lost-to-follow-up (1 subject with mild Tyndall effect and mild swelling of the lower left eyelid was last seen 71 days after ADE was identified and 1 subject with moderate bruising on the left cheek was last seen 13 days after ADE was identified) **Table 15: ADEs Sorted by Severity (Visit 1/1b to Visit 8 – Initial Treatment to 52 Weeks Follow-Up Excluding Retreatment – Pooled) – Safety Population** | From V1/1b to V8 Severity | Needle (N=116) | | Cannula (N=117) | | Total (N=233) | | | --- | --- | --- | --- | --- | --- | --- | | | Number of events | Number of subjects | Number of events | Number of events | Number of subjects | Number of events | | **Any ADE** | **28** | **22 (19.0%)** | **29** | **18 (15.4%)** | **57** | **40 (17.2%)** | | Mild | 26 | 21 (18.1%) | 27 | 16 (13.7%) | 53 | 37 (15.9%) | | Moderate | 2 | 2 (1.7%) | 2 | 2 (1.7%) | 4 | 4 (1.7%) | | Severe | 0 | 0 | 0 | 0 | 0 | 0 | Abbreviations: ADE = adverse device effect. All percentages are based on the number of subjects by group in the Safety population. ADEs with a missing severity were counted as Severe. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 26 {26} **Table 16: ADEs Sorted by Duration (Visit 1/1b to Visit 8 – Initial Treatment to 52 Weeks Follow-Up Excluding Retreatment – Pooled) – Safety Population** | From Visit 1/1b to Visit 8 | | Needle (N=116) | | Cannula (N=117) | | Total (N=233) | | | --- | --- | --- | --- | --- | --- | --- | --- | | Duration of ADE Characteristics (days) | Duration of AE (days) | Number of events | Number of subjects | Number of events | Number of subjects | Number of events | Number of Subjects | | **Any ADE** | | **28** | **22 (19.0%)** | **29** | **18 (15.4%)** | **57** | **40 (17.2%)** | | | 1-3 | 8 | 7 (6.0%) | 6 | 5 (4.3%) | 14 | 12 (5.2%) | | | 4-7 | 11 | 8 (6.9%) | 1 | 1 (0.9%) | 12 | 9 (3.9%) | | | 8-14 | 0 | 0 | 3 | 3 (2.6%) | 3 | 3 (1.3%) | | | 15 - 30 | 4 | 4 (3.4%) | 8 | 5 (4.3%) | 12 | 9 (3.9%) | | | 31 - 90 | 3 | 3 (2.6%) | 8 | 5 (4.3%) | 11 | 8 (3.4%) | | | >90 | 2 | 2 (1.7%) | 3 | 3 (2.6%) | 5 | 5 (2.1%) | | N (missing) | | 28 (0) | | 29 (0) | | 57 (0) | | | Mean (SD) | | 29.0 (67.47) | | 38.9 (41.5) | | 34.1 (55.38) | | | 95% CI Mean | | 2.8 - 55.2 | | 23.3 - 54.6 | | 19.4 - 48.7 | | | Min to Max | | 1 to 264 | | 1 to 155 | | 1 to 264 | | Abbreviations: ADE = adverse device effect. CI = Confidence Interval; Max = Maximum; Min = Minimum; SD = Standard Deviation. All percentages are based on the number of subjects by group in the Safety population. For ongoing ADEs, missing end date is assigned to date of last contact to derive current duration of the event. At time of this analysis, 1 ADE was ongoing in category 8 - 14 days, 2 ADEs were ongoing in category 31 - 90 days. ### c) Tyndall Effect Overall, the Tyndall effect was observed in seven (7) subjects: 2 in the needle subgroup and 5 in the cannula subgroup. All effects were assessed as mild. For 1 subject who was lost to follow-up, the outcome is unknown (assigned to cannula subgroup, initially in the No-Treatment control group and did not return after the 2-week visit following injection). For all other 6 subjects, the effect resolved without sequelae. ### d) Adverse Events of Special Interests (AESI) Altogether, four (4) events of visual disturbances (visual acuity reduced, headache, blurred vision, and atypical migraine) in 3 subjects were reported as Adverse Events of Special Interests (AESI), all randomly assigned to the cannula subgroup, at 2 different investigational sites. All AESIs were not related to the study devices, though the atypical migraine was possibly related to study device and unrelated to study procedure. All AESIs were mild and resolved without sequelae. There were two Serious Adverse Events (SAE) that were not device or procedure related. There were no Unanticipated Adverse Device Effects PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 27 {27} (UADE). There were no deaths, and no subjects prematurely withdrew due to an ADE. # e) **Pain at injection** Injection pain during injection (initial and retreatment) was measured using a 10cm (100mm) Visual Analog Scale (VAS), and is presented in millimeters (i.e., 100 points within the 10cm VAS). Injection pain was assessed immediately, 5, 15, and 30 minutes after filler injection. The average level of pain noted during initial injections was similar between treatment groups, with 2.2 ± 7.95 and 1.2 ± 4.52 in the needle and the cannula subgroups, respectively. Injection site pain was reduced to 0.2 ± 0.76 mm and 0.8 ± 3.52 mm in the needle and the cannula subgroups, respectively by 5 minutes post-injection. Pain at time of injection was clinically negligible on the 0-100 scale, and it continued to decrease at 5, 15 and 30 minutes following injection. There were no observable differences of reported pain between the needle and cannula subgroups. Similar findings were observed following retreatment injections. The majority of subjects did not receive pre-injection anesthesia (overall 30.5% (71/233) subjects received anesthetics) confirming that the low pain scores accurately reflect the device's pain profile. # 2. Effectiveness Results The analysis of effectiveness was based on 183 subjects who received treatment with RHA Redensity® Eye Lido and 65 subjects who were initially assigned in the No-Treatment control group 12 weeks after initial treatment. Subjects in the No-Treatment group crossed-over to receive treatment after the primary endpoint and their data were pooled for effectiveness endpoints throughout the duration of the study. Key effectiveness outcomes are presented in Table 17 to Table 21. The primary effectiveness endpoint was to assess the effectiveness (superiority) of RHA Redensity® Eye Lido versus the No-Treatment control for the correction of moderate to severe tissue volume deficiencies in the infraorbital regions at 12 weeks after the initial treatment. The effectiveness of RHA Redensity® Eye Lido was demonstrated if the responder rate for subjects treated with RHA Redensity® Eye Lido was statistically superior to the responder rate for subjects of the No-Treatment control group 12 weeks (Visit 5) after randomization as assessed by the Table 17 using the validated TIOHS. To successfully achieve the primary endpoint, the lower bound of the 2-sided 95% Confidence Interval (CI) for the responder rate for RHA PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 28 {28} Redensity® Eye Lido needed to be at least 70%, and the lower bound of the 2-sided 95% CI for the difference in the responder rate between subjects treated with RHA® Redensity Eye Lido and those in the No-Treatment control group needed to be at least 50%. The responder rate at 12 weeks after treatment and the difference of responder rate between treatment and No-Treatment groups were used to establish superiority of treatment with RHA® Redensity Eye Lido. A subject was considered a TIOHS responder if he/she presented with a ≥1-grade improvement in each of the eyes as assessed by the BLE before initial treatment and 12 weeks after the initial treatment (Visit 5). As shown in Table 17, the responder rate of subjects treated with RHA Redensity® Eye Lido was superior to that of subjects in the No-Treatment control group. In RHA Redensity® Eye Lido group, 79.0% of subjects with a 95% confidence interval [72.2% - 84.5%] responded at week 12 and thus met the first criterion (lower bound ≥70%). The responder rate in the No-Treatment control group was 9.8% [3.9 – 22.2]. The difference in the responder rate between subjects treated with RHA Redensity® Eye Lido and the No-Treatment control group was 69.3% [58.7 - 79.8], which met the second criterion (lower bound ≥50%). This difference was statistically significant (p<0.0001) for ITT population, which demonstrates the effectiveness of RHA Redensity® Eye Lido. **Table 17: Summary of TIOHS Responder Rates by BLE at Visit 5 – Multiple Imputations (ITT populations)** | Category | RHA Redensity® Eye Lido (N = 183) | No-Treatment (N = 65) | | --- | --- | --- | | N (observed cases + imputed) | 183 (173 + 10) | 65 (52 + 13) | | Responder [95% CI] | 79.0% [72.2 - 84.5] | 9.8% [3.9 - 22.2] | | Not responder | 21.0% | 90.2% | | p-value | < .0001 | | | Odds ratio RHA® Redensity Eye Lido vs No-Treatment [95% CI] | 123.84 [21.46 - 714.78] | | | Difference in responder rate (RHA Redensity Eye Lido–No-Treatment) [95% CI] | 69.3% [58.7 - 79.8] | | N = number of subjects; TIOHS = Teoxane Infraorbital Hollows Scale Note: A responder is defined as a subject with an absolute ≥1-grade improvement in each of the eyes compared to baseline on the TIOHS as assessed by BLE. For subjects lost-to-follow-up or not present at the primary endpoint visit for the TIOHS assessment, missing value is imputed using regression method within FCS for multiple imputation. Baseline is defined as the last non-missing measurement preceding the initial treatment for subjects assigned to RHA Redensity® Eye Lido and randomization date/time for subjects assigned to control groups. For achieving the superiority, observed p-value must be ≤0.025. The following 2 conditions must be met: 1) the lower bound of 2-sided 95% confidence interval for responder rate for RHA Redensity® Eye Lido is at least 70%; 2) the lower bound of 2-sided 95% confidence interval for the difference in the responder rate between subjects treated with RHA Redensity® Eye Lido and the No-Treatment control group is at least 50%. Percentages of responders and 95% CI for responders are based on the Wilson method in the article from The American Statistician, 2020, vol. 74, issue 2, 109-115. Due to the site effect on TIOHS responder rate, a logistic model was used with a p-value derived from the following model: logistic PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 29 {29} regression model by treatment arm using baseline TIOHS grade score and site as covariates. 95% CI for odds ratio were obtained using Wald method. Baseline TIOHS grade score was defined as the maximum grade at baseline between both eyes. The odds that a subject responds in RHA Redensity® Eye Lido group are 123.8 times the odds that a subject responds in No-Treatment group. 95% CI for the difference in responder rate are obtained using the Wald method. All percentages are based upon the total number of subjects with non-missing data for the TIOHS at Visit 5 after imputation. The co-primary endpoint was the change from Baseline in selected questions of the FACE-Q Appraisal of lower eyelids domain score (converted to a 0-100 scale – Rasch conversion) at 12 weeks. The effectiveness of RHA Redensity® Eye Lido was demonstrated if the modified FACE-Q Appearance of lower eyelids change from Baseline score for subjects treated with RHA Redensity® Eye Lido was statistically superior (by at least 12 points) to the subjects of the No-Treatment control group 12 weeks (Visit 5) after randomization. To successfully achieve the co-primary endpoint, the mean change from Baseline of the modified FACE-Q *Appraisal of lower eyelids* raw score for RHA Redensity® Lido needed to be $\geq 3$ and the difference between the modified FACE-Q *Appraisal of lower eyelids* change from Baseline for subjects treated with RHA Redensity® Eye Lido and the No-Treatment control group needed to be $\geq 12$. The results of the co-primary endpoint are summarized in Table 18. The modified FACE-Q *Appraisal of lower eyelids* raw score in the RHA Redensity® Eye Lido group mean change from baseline at Visit 5 was 4.8 [4.2-5.3], thereby achieving a lower bound 95% CI score that was greater than 3. The difference of the Rasch converted score between the RHA Redensity® Eye Lido treated group and the No-Treatment control group in mean change from Baseline of the modified FACE-Q was 38.8 [32.1 - 45.6], thereby achieving a lower bound for the difference that was greater than 12. **Table 18: Modified FACE-Q Change from Baseline at Visit 5: ANCOVA – Multiple Imputations (ITT)** | Category | RHA Redensity® Eye Lido N = 183 | No-Treatment N = 65 | | --- | --- | --- | | Rasch converted score at Baseline | | | | n (observed cases + imputed) | 183 (173 + 10) | 65 (52 + 13) | | Mean (SD) | 27.1 (19.78) | 32.1 (25.03) | | 95% CI Mean | 24.2 - 29.9 | 25.9 - 38.3 | | Min to Max | 0 to 73 | 0 to 100 | | Rasch converted score at Visit 5^{(a)} | | | | n (observed cases + imputed) | 183 (173 + 10) | 65 (52 + 13) | | Mean (SD) | 64.6 (22.33) | 28.0 (22.00) | | 95% CI Mean | 61.3 - 67.8 | 22.5 - 33.4 | | Min to Max | 0 to 100 | 0 to 80 | | Change from Baseline (SD) | 37.5 (27.04) | -4.1 (17.48) | PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 30 {30} | Category | RHA Redensity® Eye Lido N = 183 | No-Treatment N = 65 | | --- | --- | --- | | 95% CI Change from Baseline | 33.6 - 41.5 | -8.5 - 0.2 | | ANCOVA model at Visit 5 based on Rasch converted score | | | | H0: LS mean RHA Redensity® Eye Lido = LS mean No-Treatment 1-sided p-value | < .0001 | | | Estimate of difference in LS means | 38.8 | | | 95% CI for difference in LS means | [32.1 to 45.6] | | Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; FCS = fully conditional specification; ITT = intent-to-treat; LS = least squares; N = number of subjects; n = number of observations; SD = standard deviation Note: To successfully achieve the co-primary endpoint, the following conditions must be met: 1) the lower bound of 2-sided 95% confidence interval for the change from Baseline of the modified FACE-Q “Appraisal of lower eyelids” raw score for RHA Redensity® Eye Lido is at least 3; 2) the lower bound of 2-sided 95% confidence interval for the difference in mean change from Baseline of the modified FACE-Q between RHA Redensity® Eye Lido treated group and the No-Treatment control group is at least 12. When less than 50% of the scale’s items are missing, the mean of the completed items was used to calculate the raw score, rounded to the nearest integer. Modified 4-item FACE-Q “Appraisal of lower eyelids” is used. As ANCOVA assumptions of normality are met, p-value is derived from the following model: ANCOVA by treatment arm using baseline modified FACE-Q score and site as covariates. Baseline is defined as the last non-missing measurement preceding the initial treatment for subjects assigned to RHA Redensity® Eye Lido and randomization date/time for subjects assigned to control groups. (a) For subjects lost-to-follow-up or not present at the primary endpoint visit for the FACE-Q assessment, missing value is imputed using regression method within FCS for multiple imputation. Sensitivity analyses confirmed the robustness of the primary endpoint analysis. In summary, results support the following claim: The proportion of responders, showing ≥1-grade improvement on the TIOHS was 79.0% in the treatment group and 9.8% in the No-Treatment group, 12 weeks after injection. The results showed that treatment of the infraorbital region with RHA Redensity® Eye Lido was statistically superior to no treatment and clinically significant (p<0.0001). The mean change from Baseline of the raw score of the modified FACE-Q was 4.8 for subjects in the treatment group and -0.6 for subjects in the No-treatment group. And the difference from Baseline of the Rasch converted score was 37.5 in the treatment group and -4.1 in the No-treatment group. At 12 weeks after initial treatment, 80.9% of subjects treated with RHA Redensity® Eye Lido reported improvement in the appearance of their infraorbital region based on the study-specific FACE-Q questionnaire ‘Appraisal of lower eyelid module’, with a mean Rasch converted score increasing from 27.1 at Baseline to 64.6. The improvement in Rasch converted score at 12 weeks was statistically superior to no treatment (p<0.0001). Teoxane validated TIOHS scale was used to assess any change in the severity of the infraorbital hollows following the treatment of the PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 31 {31} infraorbital region. TIOHS change from Baseline and the responder rate were also assessed by the BLE at each visit. **Table 19: TIOHS Responder Rate (BLE) – ITT Population (Pooled)** | Visit | RHA Redensity® Eye Lido | | --- | --- | | Week 12 | 173/221 (78.3%) | | Week 24 | 159/213 (74.6%) | | Week 36 | 146/209 (69.9%) | | Week 52 | 124/205 (60.5%) | For the pooled population (248 subjects), we observed an expected slow decrease of the responder rate (BLE assessment) with time throughout the course of the study (52 weeks after last treatment). Results showed that subjects injected with RHA Redensity® Eye Lido were able to sustain infraorbital correction over time, as the correction was still visible in more than 60% of subjects at 1-year post treatment (Figure 2). There were 31.7% of subjects who presented 2-grades improvement 12 weeks after Baseline and 5.9% with 3-grades improvement. **Figure 2: TIOHS Rate of Responders (≥1-Grade Difference from Baseline), as Assessed by the Blinded Live Evaluator, through the Follow-Up Period (V5/V5b to V8) – ITT population – Pooled analysis**  The responder rate by number of grades (Table 20) showed that for the pooled population, 78.3% (173/221) of subjects had 1-grade improvement, 31.7% (70/221) of subjects had 2-grades improvements and 5.9% (13/221) had 3-grades improvements on both eyes at 12 weeks after initial treatment. And 52 weeks after treatment, 60.5% (124/205) of subjects maintained 1-grade improvement and 20.5% (42/205) maintained 2-grades improvement on both eyes. None had 3-grades improvement on both eyes. PMA P170002/S050: FDA Summary of Safety and Effectiveness Data Page 32 {32} **Table 20: TIOHS Responder Rate by Number of Grade (BLE) at 12 Weeks – ITT Population** | Visit | Category | RHA Redensity® Eye Lido (N = 221 V5; N=205 V8) | | --- | --- | --- | | Visit 5/5b (12 weeks after Initial treatment) | ≥1-grade improvement from baseline for at least one eye | 185 (83.7%) | | | ≥2-grade improvement from baseline for at least one eye | 90 (40.7%) | | | ≥3-grade improvement from baseline for at least one eye…