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Bellafill1 is an implant composed of non-resorbable polymethylmethacrylate (PMMA) microspheres, 30 to 50 microns in diameter, suspended in a water based carrier gel composed of 3.5% bovine collagen, 92.6% buffered, isotonic water for injection, 0.3% lidocaine hydrochloride, 2.7% phosphate buffer, and 0.9% sodium chloride.
1 Bellafill® formerly known as ArteFill®
Bellafill is indicated for the correction of nasolabial folds and moderate to severe, atrophic, distensible facial acne scars on the cheek in patients over the age of 21 years.
Four (4) weeks prior to treatment, patients will be given a 0.1cc test injection of Bellafill skin test material intradermally in the volar forearm, to determine a patient's sensitivity to the treatment material. For a complete discussion of the Bellafill Skin Test, refer to the Instructions for Use supplied with test syringes.
The patient should observe the test site daily during the 4-week test period and notify the physician immediately if any effects indicative of a positive or equivocal response are observed or if systemic effects are experienced. A Bellafill Skin Test Results Card should be provided to the patient at the time of the skin test to help the patient assess the test site.
A positive response consists of erythema of any degree, induration, tenderness, and swelling, with or without pruritus, which can appear immediately following implantation and persists for more than 24 hours or appears more than 24 hours following implantation for any length of time.
An equivocal response is one in which there is no localized skin reaction, but the patient does elicit a possible systemic reaction such as a rash, arthralgia (aching joints), or myalgia (aching muscles) that occurs at any time during the 4-week observation period. If an equivocal response is observed, a second injection in the opposite arm is required, with observation for an additional 4 weeks. Patients demonstrating a positive or equivocal response in this second test should not be treated.
Bellafill is indicated for the correction of nasolabial folds and moderate to severe, atrophic, distensible facial acne scars on the cheek in patients over the age of 21 years.
Bellafill is an aseptic product that is required to pass a USP sterility test before release. It is supplied in a sealed tray containing individual treatment syringes with sterile needles for single patient use, packaged in a box. Each syringe contains: 20% polymethylmethacrylate microspheres and 80% bovine collagen solution containing 3.5% bovine collagen, 2.7% phosphate buffer, 0.9% sodium chloride, 0.3% lidocaine hydrochloride, and 92.6% water for injection.
The tray lid and tip of each individual syringe is sealed with a tamper evidence cover. Do not use if the tamper evidence cover is broken or removed. Do Not Sterilize.
Bellafill should be stored at standard domestic refrigerator temperatures. DO NOT FREEZE.
Bellafill has an off-white appearance. In the event that the content of a syringe shows signs of separation and/or is clear (like water), do not use the syringe and notify Suneva Medical immediately. In the United States or Canada, call toll-free 888-278-3345. Outside the United States or Canada call +1-858-550-9999.
SUNEVA MEDICAL, Inc. 5870 Pacific Center Blvd. San Diego, CA 92121, United States of America. Revised: N/A
All adverse events (AEs), including those attributed and not attributed to treatment, reported in Bellafill or Control subjects at an incidence of 1% or greater in U.S. studies are presented in Table 1 below in descending order according to frequency in the Bellafill group.
Table 1: Adverse Events Reported at an Incidence of 1% or Greater in U.S. NASOLABIAL fold clinical trials of Bellafill
| Event | Number of Events (Events/subjects treated, %) | ||
| Bellafill1 n = 285 |
Bellafill2 n = 106 |
Control3, 4 n = 123 |
|
| Lumpiness at injection area more than one month after injection | 13 (4.6) | 4 (3.3) | |
| Persistent swelling or redness | 10 (3.5) | 3 (2.8) | 13 (10.6) |
| Increased sensitivity | 5 (1.8) | 2 (1.9) | |
| Rash, itching more than 48 hours after injection | 4 (1.4) | 2 (1.6) | |
| Sensitization reactions | 6 (4.9) | ||
| Abscess | 3 (2.4) | ||
| Visibility of puncture area | 2 (1.6) | ||
| 1128 Bellafill subjects in the controlled study and 157 subjects in an open label study, who were followed for 1 year after implantation. 2106 Control subjects who received Bellafill in the cross-over arm of the controlled study and were followed for 6 months after implantation. 3123 subjects who received the Control treatment in the controlled study and were followed for 6 months after implantation. 4 The Control treatment in study was a commercially available collagen implant (Zyplast®). |
|||
No systemic adverse events were reported at an incidence of 1% or greater. One severe adverse event (granuloma or enlargement of the implant) and 14 moderate adverse events (persistent swelling or redness, lumpiness at injection site more than 1 month after injection, blurred vision, flu-like symptoms, abscess, granuloma or enlargement of the implant, alopecia areata) were reported for Bellafill subjects. Nine severe adverse events (lumpiness at injection site more than 1 month after injection, abscess, infection, granuloma or enlargement of the implant, sensitization reactions, increased sensitivity, persistent swelling or redness), and 12 moderate adverse events (persistent swelling or redness, rash, itching more than 48 hours after injection, sensitization reactions, lumpiness at injection site more than 1 month after injection, visibility of the puncture area, abscess) were reported for Control subjects.
Local adverse events reported in Bellafill subjects at an incidence of less than 1% in US studies, whether or not they were determined to be related to the implant, were sensitization reactions, abscess, visibility of the puncture area, blurred vision, flu-like symptoms, recurrence of existing herpes labialis, granuloma or enlargement of the implant, acneiform lesions, occasional tenderness, redness and visible capillaries, alopecia areata, and dry skin.
Systemic adverse events reported at an incidence of less than 1% were mild chest congestion and fainting. One subject was diagnosed with breast cancer, determined by the investigator not to be related to the implant.
For Control subjects, local adverse events reported at an incidence of less than 1%, whether or not they were determined to be related to the implant, were increased sensitivity, flu-like symptoms, granuloma or enlargement of the implant, infection, and acneiform reaction. One subject died of trauma unrelated to the implant.
The following is a summary of the reported duration of adverse events lasting longer than 2 weeks in Bellafill subjects (n=391 subjects) in US studies: lumpiness at injection site more than 1 month after injection (n=12 events), duration varied from 4 weeks to unresolved at 26 weeks; persistent swelling or redness (n=8 events), duration varied from 5 weeks to unresolved at 26 weeks; increased sensitivity (n=7 events), duration varied from 4 weeks to unresolved at 26 weeks; rash and itching (n=2 events), duration varied from 3 weeks to 6 weeks; sensitization reactions (n=2 events), duration varied from 19 weeks to unresolved at 26 weeks; visibility of the puncture site (n=1 event), duration was 13 weeks; granuloma or enlargement of the implant (n=4 events), duration varied from 10 weeks to unresolved at 26 weeks; other local complications (n=5 events), duration was unresolved at 26 weeks. One subject suffered from breast cancer unrelated to the implant.
Reported duration of adverse events lasting longer than 2 weeks in Control subjects (n=123 subjects): lumpiness at injection site more than 1 month after injection (n=2 events), duration varied from 13 weeks to unresolved at 26 weeks; persistent swelling or redness (n=12 events), duration varied from 7 weeks to unresolved at 26 weeks; increased sensitivity (n=1 event), duration was unresolved at 26 weeks; rash and itching (n=2 events), duration was unresolved at 26 weeks; sensitization reactions (n=4 events), duration varied from 7 weeks to unresolved at 26 weeks; abscess (n=2 events), durations were unresolved at 26 weeks; visibility of the puncture site (n=1 event), duration was unresolved at 26 weeks; granuloma or enlargement of the implant (n=1 event), duration was unresolved at 26 weeks; flu-like symptoms (n=1 event), duration was unresolved at 26 weeks. One subject died from an accident unrelated to the implant.
Among the 391 subjects treated with Bellafill, adverse events with reported onset dates 3 months or more after treatment were lumpiness at the injection site (6), rash and itching (3), sensitization reaction (2), increased sensitivity (2), persistent swelling and redness (1), granuloma or granulomatous inflammation (1), alopecia areata (1), visibility of the puncture site (1), and redness and visible capillaries near the area of injection (1).
Among the 123 Control subjects, adverse events with reported onset dates 3 months or more after treatment were abscess (1), infection (1), lumpiness (1), acneiform reaction (1), flu-like symptoms (1), persistent swelling or redness (1), and trauma fatality not related to the implant (1).
The U.S. Acne Scar pivotal study (Study SUN-11-001) involved 147 treated subjects at 10 centers. At baseline, subjects were randomized to receive Bellafill in the cheeks or Saline (Control group). At 6 months, all Control subjects were eligible to receive treatment with Bellafill.
Of the 147 subjects treated in the study, 143 subjects received a treatment with Bellafill at either baseline/Day 0 (Period I) or at Month 6 (Period II, Track B). Therefore the safety information reflects the combination of patient outcomes for the initial (n=97) and cross-over (n=46) Bellafill subjects (i.e., 97 + 46 = 143 total) compared to the 50 subjects who were initially enrolled in the control treatment arm.
Subjects were asked to keep diary cards and grade symptoms of erythema, swelling, bruising, pain, itching, lumps/bumps and discoloration. Subjects’ scores for the severity of these events after initial treatment are presented in Table 2 and durations are provided in Table 3, respectively. Subjects who observed any signs or symptoms (89.2%), experienced them shortly after Bellafill treatment and the majority were mild to moderate in intensity. Subjects typically reported these diary card symptoms as resolved in 1-7 days. Similar subject diary outcomes were noted following touch-up treatment injections.
Table 2: Maximum intensity of Signs/Symptoms after Initial Bellafill Treatment from  Subject Diary (n=130)*
| Sign/symptom (R&L side combined) | None n(%) |
Mild n(%) |
Moderate n(%) |
Severe n(%) |
| Any sign/symptom | 14 (10.8%) | 54 (41.5%) | 51 (39.2%) | 11 (8.5%) |
| Swelling | 40 (30.8%) | 48 (36.9%) | 38 (29.2%) | 4 (3.1%) |
| Erythema | 44 (33.8%) | 60 (46.2%) | 23 (17.7%) | 3 (2.3%) |
| Pain | 47 (36.2%) | 52 (40.0%) | 28 (21.5%) | 3 (2.3%) |
| Bruising | 53 (40.8%) | 49 (37.7%) | 23 (17.7%) | 5 (3.8%) |
| Lumps/bumps | 55 (42.3%) | 45 (34.6%) | 27 (20.8%) | 3 (2.3%) |
| Itching | 97 (74.6%) | 26 (20.0%) | 7 (5.4%) | 0 (0.0%) |
| Discoloration | 102 (78.5%) | 21 (16.2%) | 6 (4.6%) | 1 (0.8%) |
| * # treated subjects returning diaries, combined for Period I and Period II data | ||||
Percentages are based on the number of subjects returning diaries
Table 3: Duration of Signs/Symptoms after Initial Bellafill Treatment from Subject Diary (n=130)*
| Sign/symptom (R&L side combined) | Any | 1day | 2-7days | 8-14days |
| Any sign/symptom | 116 (89.2%) | 7 (5.4%) | 61 (46.9%) | 48 (36.9%) |
| Erythema | 86 (66.2%) | 34 (26.2%) | 39 (30.0%) | 13 (10.0%) |
| Swelling | 90 (69.2%) | 15 (11.5%) | 65 (50.0%) | 10 (7.7%) |
| Bruising | 77 (59.2%) | 7 (5.4%) | 44 (33.8%) | 26 (20.0%) |
| Pain | 83 (63.8%) | 17 (13.1%) | 57 (43.8%) | 9 (6.9%) |
| Itching | 33 (25.4%) | 10 (7.7%) | 19 (14.6%) | 4 (3.1%) |
| Lumps/bumps | 75 (57.7%) | 14 (10.8%) | 44 (33.8%) | 17 (13.1%) |
| Discoloration | 28 (21.5%) | 5 (3.8%) | 13 (10.0%) | 10 (7.7%) |
| * # treated subjects returning diaries, combined for Period I and Period II data  Percentages are based on the number of subjects returning diaries | ||||
46/143 of the Bellafill and 16/50 of the Control subjects experienced at least one all cause (related and unrelated) Treatment-Emergent Adverse Event (TEAEs). TEAEs that occurred in ≥ 4% of the subjects (related and unrelated) (i.e., 51/143 of the Bellafill and 12/50 of the Control subjects) are presented below in Table 4
Table 4: Treatment-Emergent AEs in ≥ 4% of the subjects sorted by system organ class (SOC) and preferred term
| System organ class code | Preferred Term (PT) | Bellafill n=143* |
Control n=50 |
||
| Subjects | Events | Subjects | Events | ||
| General disorders and administration site conditions | 22 (15.4%) | 27 | 1 (2.0%) | 1 | |
| Burning sensation | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Device breakage | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Fatigue | 2 (1.4%) | 2 | 0 (0.0) | 0 | |
| Injection site bruising | 3 (2.1%) | 3 | 0 (0.0) | 0 | |
| Implant site mass | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Injection site discoloration | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Injection site pain | 3 (2.1%) | 3 | 0 (0.0) | 0 | |
| Injection site reactions | 6 (4.2%) | 6 | 0 (0.0) | 0 | |
| Pruritus | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Swelling | 3 (2.1%) | 3 | 0 (0.0) | 0 | |
| Tenderness | 5 (3.5%) | 5 | 1 (2.0%) | 1 | |
| Infections and infestations | 14 (9.8%) | 16 | 4 (8.0%) | 6 | |
| Bacterial infection | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Bronchitis | 0 (0.0) | 0 | 1 (2.0%) | 1 | |
| Ear infection | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Hordeolum | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Influenza | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Influenza like illness | 2 (1.4%) | 2 | 2 (4.0%) | 3 | |
| Meningitis | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Nasopharyngitis | 4 (2.8%) | 4 | 0 (0.0) | 0 | |
| Oral infection | 0 (0.0) | 0 | 1 (2.0%) | 1 | |
| Pharyngitis | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Pharyngitis streptococcal | 1 (0.7%) | 1 | 1 (2.0) | 1 | |
| Sinusitis | 2 (1.4%) | 2 | 0 (0.0) | 0 | |
| Skin papilloma | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Musculoskeletal and connective tissue disorders | 5 (3.5%) | 5 | 5 (10.0%) | 5 | |
| Arthralgia | 2 (1.4%) | 2 | 0 (0.0) | 0 | |
| Back pain | 2 (1.4%) | 2 | 2 (4.0%) | 2 | |
| Hand fracture | 0 (0.0) | 0 | 1 (2.0%) | 1 | |
| Pain in extremity | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Tendonitis | 0 (0.0) | 0 | 1 (2.0%) | 1 | |
| Wrist fracture | 0 (0.0) | 0 | 1 (2.0%) | 1 | |
| Skin and subcutaneous tissue disorders | 10 (6.9%) | 15 | 2 (4.0%) | 2 | |
| Acne | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Actinic keratosis | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Dermatitis atopic | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Dermatitis contact | 2 (1.4%) | 0 (0.0) | 0 | ||
| Erythema | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Herpes Zoster | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Papule | 1 (0.7%) | 1 | 1 (2.0%) | 1 | |
| Rash | 2 (1.4%) | 0 (0.0) | 0 | ||
| Seborrhoeic dermatitis | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Squamous cell carcinoma of skin | 1 (0.7%) | 1 | 0 (0.0) | 0 | |
| Urticaria | 1 (0.7%) | 1 | 1 (2.0%) | 1 | |
| * n=143 is based on 97 Subjects treated Bellafill from study Period I and 46 Period II Control subjects that crossed over and were treated with Bellafill | |||||
Five serious adverse events (SAEs) were noted during the study; cholecystitis, lower back nerve impingement, recurrence of breast cancer, West Nile meningitis and exacerbation of depression. None were deemed related to study treatment. There were no deaths during the study.
Adverse events of special interest were followed separately for the study. These included hyper and hypopigmentation, hypertrophic scarring or keloid formation and the appearance of granulomas. None of these adverse events were reported.
14 Bellafill and no Control subjects experienced treatment-related adverse events (TRAEs). Twelve (12) adverse events were mild, one (1) case of injection site reaction was moderate in severity, and one (1) injection site bruising was severe in intensity. Eleven (11) events resolved and three (3) cases of injection site reaction (lumpiness directly after injection) persisted throughout the study. Two (2) of these events were deemed by the investigator to be mild and one event was deemed to be of moderate severity. All treatment- related adverse events (TRAEs) reported in Bellafill subjects by severity and duration are presented in Tables 5 and 6, respectively.
Table 5: Summary of TRAE (by Severity)
| System Organ Class | Preferred Term | Subject (n=143) |
Events |
| Any TRAE | 14 (9.8%) | 14 | |
| Mild | 12 (8.4%) | 12 | |
| Moderate | 1 (0.7%) | 1 | |
| Severe | 1 (0.7%) | 1 | |
| General disorders and administration site conditions | |||
| Implant site mass | 1 (0.7%) | 1 | |
| Mild | 1 (0.7%) | 1 | |
| Moderate | 0 | 0 | |
| Severe | 0 | 0 | |
| Injection site pain | 3 (2.1%) | 3 | |
| Mild | 3 (2.1%) | 3 | |
| Moderate | 0 | 0 | |
| Severe | 0 | 0 | |
| Injection site reactions (i.e., lumpiness and papule formation) | 4 (2.8%) | 4 | |
| Mild | 3 (2.1%) | 3 | |
| Moderate | 1 (0.7%) | 1 | |
| Severe | 0 | 0 | |
| Swelling | 1 (0.7%) | 1 | |
| Mild | 1 (0.7%) | 1 | |
| Moderate | 0 | 0 | |
| Severe | 0 | 0 | |
| Injection site bruising | 3 (2.1%) | 3 | |
| Mild | 2 (1.4%) | 2 | |
| Moderate | 0 | 0 | |
| Severe | 1 (0.7%) | 1 | |
| Tenderness | 1 (0.7%) | 1 | |
| Mild | 1 (0.7%) | 1 | |
| Moderate | 0 | 0 | |
| Severe | 0 | 0 | |
| Skin and subcutaneous tissue disorders | |||
| Acne | 1 (0.7%) | 1 | |
| Mild | 1 (0.7%) | 1 | |
| Moderate | 0 | 0 | |
| Severe | 0 | 0 | |
Table 6: Summary of TRAE (by Duration)
| SOC/PT | Subject (n=143) |
Events | |
| Any TRAE | n | 14 | 14 |
| Mean # days (SD) | 30.8 (53.8) | ||
| Median (min.max) | 16 (1,180) | ||
| General disorders and administration site conditions | |||
| Implant site mass | n | 1 | 1 |
| Mean # days (SD) | 180 (0) | ||
| Median (min.max) | 180 (180,180) | ||
| Injection site pain | n | 3 | 3 |
| Mean # days (SD) | 3.7 (1.5) | ||
| Median (min.max) | 4 (2,5) | ||
| Injection site reactions (i.e., lumpiness and papule formation) | n | 4* | 4 |
| Mean # days (SD) | 76 (0) | ||
| Median (min.max) | 76 (76,76) | ||
| Swelling | n | 1 | 1 |
| Mean # days (SD) | 1 (0) | ||
| Median (min.max) | 1 (1,1) | ||
| Injection site bruising | n | 3 | 3 |
| Mean # days (SD) | 17.3 (0.6) | ||
| Median (min.max) | 17 (17,18) | ||
| Tenderness | n | 1 | 1 |
| Mean # days (SD) | 3 (0) | ||
| Median (min.max) | 3 (3,3) | ||
| Skin and subcutaneous tissue disorders | |||
| Acne | n | 1 | 1 |
| Mean # days (SD) | 16 (0) | ||
| Median (min.max) | 16 (16,16) | ||
| * Data doesn’t include 3 subjects each with 1 unresolved event | |||
Since product approval for the correction of nasolabial folds, the adverse events received via Bellafill post-marketing surveillance in on-label or off-label settings were infrequent. Those events that were reported in five or more instances include (in order of decreasing frequency reported) lumps/bumps, swelling, nodules, bruising, granuloma, redness, and reported allergic reactions. Time to onset for these events ranged from immediate to three and a half years post-injection. The majority of the events, (when severity was reported) were mild in severity and no events were characterized as serious. Outcomes for these events ranged from resolution to ongoing at the time of last contact. The treatments for these events included massage, ice packs, warm compress, antibiotics, antihistamines, various energy treatments, oral and intralesional steroids, and device excision.
Adverse events possibly related to intravascular injection have been reported. Symptoms ranged from possible skin discoloration to bumps to skin necrosis. Time of onset, (when known), ranged from the day of injection to 3 days post treatment. The majority of the intravascular injection events were mild in severity and no events were reported as serious. Treatments included nitroglycerin paste, aspirin, and warm compresses. These events resolved or were resolving within one month after onset.
A single case of blindness was reported as a Medical Device Report (MDR) after Bellafill injection. The patient was injected in the right canthal area (periorbital), and experienced immediate onset of loss of vision in the right eye. Treatments included IV saline, direct pressure release in the anterior chamber of the eye and treatment in a hyperbaric oxygen chamber. The patient’s vision did not return. In this patient case, periorbital injection of Bellafill was outside the recommended Indications for Use (see WARNINGS section).
Adverse reactions should be reported to Suneva Medical, Inc. at 1-858-550-9999.
A prospective, multi-center, double-masked, randomized trial compared Bellafill and a commercially available collagen implant for the treatment of soft tissue defects of the face. A total of 251 (i.e., 128 Bellafill and 123 Control) subjects were enrolled and the nasolabial folds of 212 (i.e., 108 Bellafill and 104 Control) subjects were treated.
The primary effectiveness endpoint was a comparison of the cosmetic correction provided by Bellafill and Control treatments at the end of a 6 month period after injection, evaluated by means of a validated facial fold assessment scale (FFA Scale) using standardized photographs as reference.
The numerical values for FFA Scale were: zero – no folds; one – folds just perceptible (i.e., ~0.1 mm); two – shallow folds with some defined edges (i.e., ~0.2 mm); three – moderately deep folds with some well-defined edges (i.e., ~0.5 mm); four – deep folds with most edges well-defined and some redundant folds (i.e., ~1.0 mm) and five – very deep folds with most edges well-defined and some redundant folds (i.e., ~2.0 mm). Comparisons to the reference photos were made at pre-treatment and at each follow-up visit. Safety was evaluated by comparing the incidence and severity of clinical events during and for 12 months after treatment completion.
Subject and Baseline Characteristics are presented in Table 7.
Table 7: Subject and Baseline Characteristics
| Demographic | Bellafill (n = 128) |
Control (n = 123) |
| Gender | ||
| Male | 11 (8.6%) | 11 (8.9%) |
| Female | 117 (91.4%) | 112 (91.1%) |
| Age, years | ||
| Mean | 53.2 | 51.2 |
| Range | 28-82 | 29-78 |
| Ethnicity | ||
| Caucasian | 100 (78.1%) | 101 (82.1%) |
| Hispanic | 21 (16.4%) | 20 (16.3%) |
| Asian | 1 (0.8%) | 1 (0.8%) |
| Other1 | 6 (4.7%) | 1 (0.8%) |
| Facial Area Treated | ||
| Nasolabial Folds | 108 (84.4%) | 104 (84.6%) |
| Wrinkle Severity | Mean Value | Mean Value |
| Nasolabial Folds2 | 1.74 | 1.45 |
| 1 “Other” ethnicities, as reported by Bellafill subjects, were Mexican/Greek/English, Italian, Hispanic/Irish, American Indian, Native American, Middle Eastern. “Other” ethnicity, as reported by a Control subject, was Persian. 2 Subjects in the Bellafill treated group had a higher baseline fold severity than those in the Control group. The difference was statistically significant (p=0.039). |
||
The mean improvement in nasolabial fold wrinkle severity, as characterized by the masked observers, for subjects from before treatment to 6 months after completion of treatment was Bellafill - 0.77 points, and Control - 0.00 points. The difference was statistically significant (p = < 0.001).
At 1 month after treatment, 0.75 points (Bellafill) and 0.74 points (Control) differences from baseline for nasolabial fold wrinkle severity were recorded. At 3 months after treatment, differences of 0.81 points (Bellafill) and 0.15 points (Control) were determined for nasolabial folds. At 12 months after treatment, a nasolabial wrinkle severity difference of 0.98 points (compared to baseline) was recorded for Bellafill subjects. No assessment of nasolabial fold wrinkle severity was performed at 12 months after treatment for Control subjects.
The number of treatment sessions and volumes administered in nasolabial folds over the course of the study are displayed in Table 8 and 9, respectively.
Table 8: Mean Number of Treatment Sessions per Product
| Area | Bellafill | Control |
| Nasolabial Folds | 2.28 (n=108) | 2.18 (n= 104) |
Table 9: Mean Volume of Product used per Side (Left/Right)
| Treatment Area | Bellafill (cc) | Control (cc) |
| Nasolabial Folds | 0.82 (n=108) | 1.46 (n= 104) |
This open-label, single-arm, multi-center study assessed the safety of Bellafill injections for the correction of soft tissue defects of the face. 157 subjects were enrolled and monitored at 3, 6, and 12 months post-treatment. 126/157 (80.2%) subjects completed the 1-year study. The safety data collected in this study were included in Table 1.
A prospective, multi-center, randomized, double-blind, controlled trial assessing the efficacy and safety of Bellafill for the correction of facial atrophic acne scars was conducted. A total of 147 (97 Bellafill and 50 Saline Control) subjects were enrolled and treated in the controlled phase of the study.
The primary effectiveness endpoint was a responder analysis in which the criteria for success at 6 months was defined as 50% or more of treated scars improving by 2 or more points, based on the blinded investigator assessment utilizing the validated 4-point Acne Scar Rating Scale (ASRS). The objective was to show that Bellafill was superior to Control in treating acne scars. The ASRS (Table 10) is a four point, static scale ranging from minimal to severe that relies on the depth of individual scars for severity assessment.
Table 10: Acne Scar Rating Scale (ASRS)
| Score | Description |
| 1 | Minimal or None - Depth up to 0.5mm in depth. Visibility = Perceptible with tangential lighting |
| 2 | Mild - Depth >0.5mm to <1.5mm in depth. Visibility = Moderately Detectable with tangential lighting |
| 3 | Moderate - Depth = ≥1.5mm to <2.5mm in depth. Visibility = Easily seen with tangential lighting |
| 4 | Severe - Depth = ≥2.5 mm in depth. Visibility = Substantial shadowing with tangential lighting |
Subject and Baseline Characteristics are presented in Table 11.
Table 11: Subject and Baseline Characteristics
| Demographic | Bellafill (n = 97) |
Control (n = 50) |
| Gender | ||
| Male | 37 (38.1%) | 20 (40.0%) |
| Female | 60 (61.9%) | 30 (60.0%) |
| Age, years | ||
| Mean | 44.6 | 45.3 |
| Range | 21-67 | 22-63 |
| Race | ||
| Caucasian | 70 (72.2%) | 38 (76.0%) |
| Black | 20 (20.6%) | 8 (16.0%) |
| American Indian/native Alaskan | 2 (2.1%) | 0 (0.0%) |
| Native Hawaiian/Pacific Islander | 1 (1.0) | 0 (0.0%) |
| Asian | 4 (4.1) | 4 (8.0%) |
| Other | 0 (0.0%) | 0 (0.0%) |
| Ethnicity | ||
| Non-Hispanic | 77 (79.4%) | 37 (74.0%) |
| Hispanic | 20 (20.6%) | 13 (26.0%) |
The number and severity of scars per subject are shown in Table 12. There were no differences between treatment groups regarding the number of qualifying scars or their severity. The median number of scars to be treated for each subject was 8.0 in each group with a median Acne Scar Rating Scale (ASRS) severity of 3.2 in each group.
Table 12: Acne Scar Characteristics at Baseline
| Number and Severity of Scars | Bellafill (n = 97) |
Control (n = 50) |
|
| Number of qualified scars/subject | N | 97 | 50 |
| Mean ± SD | 8.9 ± 4.6 | 8.5 ± 3.7 | |
| Mean scar severity | N | 97 | 50 |
| Mean ± SD | 3.3 ± 0.3 | 3.3 ± 0.3 | |
| Average volume/subject (mL) -Total | N | 97 | 50 |
| Mean ± SD | 1.50 ± 1.03 | 2.61 ± 1.80 | |
| Note: Mean ± standard deviation. | |||
The primary effectiveness endpoint was analyzed as a responder analysis, in which the criterion for success was defined as 50% or more of treated scars on a patient improved by two or more points on the ASRS at the 6 month visit (as evaluated by a live blinded evaluator). The observed success rate at 6 months in the Bellafill group was 56/87 (64%) and significantly higher (p=0.0005) than in the Control group 15/46 (33%).
Bellafill was found to be effective in all Fitzpatrick skin types, and for male subjects as well as female subjects.
A secondary effectiveness endpoint was a responder analysis (i.e., success was defined as 50% or more of treated scars on a patient improved by two or more points) determined via ASRS at each time point by a live blinded evaluator. The observed success rates in unblinded assessments at 9 and 12 months for the Bellafill group were 48/78 (61.5%) and 58/82 (70.7%). See Figure 1.
Figure 1: Proportion (%) of Responders Assessed by the Blinded Evaluator Based on the Observed Estimate
 |
In addition to assessing patient responder rates, the response rate of individual scars was also compared. In this analysis where scars with a greater than or equal to a two-point improvement on the ASRS over baseline were considered responders, 442/789 (56.0%) of scars in the Bellafill group and 118/397 (29.7%) of scars in the Control group were judged as successes. Bellafill injections were superior to Control treatment at all study visits after the Week 4 touch-up injection.
Independent masked review of photographs (IPR) from the 6 Month visit by three board-certified physicians revealed a higher ASRS response rate for Bellafill than Control subjects, but these rates were lower than those determined by live Blinded Evaluators.
Subjects blinded to the treatment rated the overall degree of improvement in their treated scars using a five point, non-validated Subject Global Aesthetic Improvement Scale (SGAIS) where 5 was “much improved”, 3 was “no change” and 1 was “much worse.” Seventy-seven percent (77.0%) of subjects (67/87) treated with Bellafill and forty-one percent (41.3%) treated with Control (19/46) reported improvement in their global appearance at 6 months after their injection. Subjects who were treated with Bellafill continued to report improvement in their global appearance in an unblinded assessment at month 9 (84.6%) 66/78 and at month 12 (83.1%) 69/83.
The benefits as determined by the improvements seen on the Acne Scar Rating Scale and patient satisfaction scale as well as the risks as assessed from short term adverse outcomes seen after injection and rare late adverse events, are sufficiently well understood for patients to make informed decisions about device use.
All subjects were required to have a skin test prior to being considered for injection with Bellafill.
Results Of The Skin Tests
In the randomized NLF study, there were no positive skin tests in the 128 patients first randomized to receive Bellafill treatment or the 106 Control subjects who elected to receive Bellafill injections in the cross-over cohort. Of the 141 subjects who received the collagen Control skin test, 6 had a positive skin test and were excluded from the study.
Serum IgG
In the randomized NLF study, 4 Bellafill and 2 Control subjects were not treated because they displayed abnormal baseline serum IgG levels against collagen during screening. One subject in the Bellafill group transitioned from a normal IgG level before administration of the skin test to a value above the normal range at 1 month after treatment. This subject’s IgG levels returned to the normal range by 3 months after treatment.
Acne Scar Study
175 subjects received the Bellafill skin test. Three subjects (1.7%) demonstrated a positive skin test, and were excluded.
A complete medical history should be obtained to determine whether the patient is an appropriate candidate for treatment with Bellafill.
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