A SuppleMeNt to JDD. Not Copy. Correction With a Ribose Cross-linked Collagen Dermal Filler. Penalties Apply

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1 A SuppleMeNt to JDD Lip Do Augmentation Not Copy and Contour Correction With a Ribose Cross-linked Collagen Dermal Filler ISSN: March 2009 Volume 8 Issue 3 (Su p p l e m e n t)

2 This supplement to the Journal of Drugs in Dermatology is supported by a medical education grant from

3 Lip Augmentation and Contour Correction With a Ribose Cross-linked Collagen Dermal Filler Koen De Boulle MD, a Sandra Swinberghe, b Marie Engman, c David Shoshani d AbstrAct March Volume 8 Issue 3 (supplement) CopyrIght 2009 ORiginAL ARtiCLes Journal of Drugs In Dermatology a. Aalst Dermatology Clinic, Aalst, Belgium b. ADC Dermatology, Antwerpen, Belgium c. Nackakliniken, Nacka, Sweden d. ColBar LifeScience Ltd, Herzliya, Israel Background: Dermicol-P35 is a collagen gel for soft-tissue cosmetic correction. This study evaluated the affects of Dermicol-P35 in patients who underwent lip enhancement. Methods: This open, multicenter, retrospective data collection study included patients who received an injection of Dermicol-P35 30G to the lip. All patients who had undergone Dermicol-P35 30G lip injections at 3 cosmetic clinics in Europe were identified and evaluated for inclusion in the study. Assessments were conducted by a clinic investigator immediately after the initial injections and after any touch-up injections as well as 4 months to 10 months after the initial injection. Efficacy measures included subjective impression of improvement by the clinic investigator who performed the injections, and subjective satisfaction of both the investigator and patient with treatment. Safety measures included any adverse events, and the occurrence of swelling, bruising, lumpiness, and pain. Results: Fifty-seven patients were identified to have undergone lip injections, and 51 of these patients met criteria for inclusion in the study. Four months to 10 months postinjection, most patients (98%) were believed to have an improvement in lip enhancement, and the clinic investigators rated themselves as very satisfied or satisfied with 90% of the treatment results. The majority of patients (94%) were either very satisfied or satisfied with the Dermicol-P35 30G enhancement. The majority of treatments elicited no reports of swelling, bruising, or lumpiness. Conclusion: These study results support Dermicol-P35 30G treatment as a safe and effective treatment for lip enhancement. IntroductIon Soft-tissue augmentation has become increasingly important as more patients seek aesthetic improvement without major surgical procedures. Today, there is an increasing demand for soft-tissue augmentation specifically requested for lip enhancement and augmentation. 1 Lip augmentation requires a thorough understanding of anatomy, aesthetic balance, and expertise with different dermal-filling agents. Dermicol-P35 30G (EVOLENCE BREEZE, ColBar LifeScience Ltd, Herzliya, Israel) is a collagen gel developed for the cosmetic correction of soft-tissue contour deficiencies and deformities. The porcine collagen in Dermicol-P35 (available in 27G and 30G formulations) is cross-linked utilizing the patented GLYMATRI (ColBar LifeScience Ltd) technology that uses a naturally occurring sugar metabolite. 6 The process begins with Penalties the extraction Apply and breakdown of porcine collagen into pure collagen molecules. The antigenic parts of these molecules (telopeptides) are then removed with pepsin treatment, thus pre- In 2004, a 4-group classification was proposed for soft-tissue fillers: nonpermanent biodegradable, semi-permanent or venting antigenic reactions on injection. stimulatory biodegradable, permanent reversible, and permanent nonreversible. 2 In the group of nonpermanent biodegradable agents, the most popular agents for lip augmenta- products has shown that products possessing extensive cross- Preclinical and clinical experience with these collagen medical tion and reshaping are bovine collagen, human collagen (in linking tend to have slower resorption rates in vivo, which may the United States), hyaluronic acid, and purified porcine collagen. As the major structural protein in the body s soft tissues, study of Dermicol-P30 (30 mg/ml), glutaraldehyde cross-linked be associated with a prolonged clinical effect. In a comparison collagen is a natural choice for lip augmentation and has been collagen, and non cross-linked collagen injected into rabbit ears, the gold standard for dermal fillers over the past 25 years. 3 the ribose-linked collagen retained its 3-dimensional shape for However, the use of bovine collagen is limited by the possibility of allergic hypersensitivity reactions, characterized by after 6 months. 7 In a clinical trial comparing Dermicol-P30 with greater than 12 months, whereas the others lost their shape symptoms such as long-term erythema, induration, swelling, bovine cross-linked collagen injected into the nasolabial fold of and pruritus, 4 and therefore requires skin testing, which can volunteers, the porcine collagen was superior in the improvement of wrinkle severity, with an average follow-up of up to result in a delay in treatment. Further, both bovine collagen and human collagen are associated with a poor persistence of 18 months (P =.022). 8 Thus, Dermicol-P35 may fill skin-contour the cosmetic effect. 5 defects for longer periods of time compared to other currently

4 2 available commercial filler products. In addition, Dermicol-P35 has been shown to have a low potential for hypersensitivity. 9 Dermicol-P35 30G is currently available in the European region, Canada, Israel, South Africa, and Asia (Japan, South Korea). Dermicol-P35 27G is available worldwide but is not intended for use in lips or vermilion border enhancement. The objective of this retrospective study was to subjectively evaluate the safety and performance of Dermicol-P35 30G injections in patients who underwent treatment for lip enhancement. Methods Study Design This was an open, multicenter, retrospective data collection study to evaluate the performance and safety of Dermicol-P35 for lip enhancement in patients who had clinical evidence of lip volume loss. Data were collected from patients who received at least 1 injection of Dermicol-P35 30G (35 mg/ml) to enhance or restore the contour of the upper and/or lower lip in either the vermilion border, the body of the lip, or both. Data were collected from 3 aesthetic dermatology/surgery clinics in Europe (2 in Belgium and 1 in Sweden). Clinics were identified and selected based on their experience with Dermicol-P35 30G; each selected clinic had a minimum of 10 treated cases within 4 months to 10 months prior to the onset of the study. Each clinic had a physician (De Boulle, Swinberghe; Belgium) or a registered nurse (Engman, Sweden) who participated as an investigator in the study. All patients who had received lip injection treatment as specified 4 months to 10 months prior to the onset of the study were identified by the clinic investigators and evaluated for study inclusion based on the defined inclusion and exclusion criteria. Patients who met study criteria were contacted in order to receive informed consent for the program. Once the patient s informed consent was given, the clinic investigator performed a 4-month to 10-month follow-up assessment. All patients were enrolled between March 16, 2007 and June 5, In total, assessments were conducted at 3 time points: screening and initial injection (designated as visit 1 and visit 2), a touch-up visit (if a touch-up was required) (designated as visit 3 and visit 4), and a long-term follow-up assessment (designated as visit 5) that occurred 4 months to 10 months after the initial injection. If a touch-up was required, it was to have been performed more than 4 months prior to the onset of the study. Available data were obtained directly from the clinic investigators who performed the injection and their clinical records. After enrollment in the study, the patients returned to the clinic to provide informed consent and to complete the 4-month to 10-month assessment. Study Population The study population included healthy patients 25 years of age, male or female, who desired lip enhancement and/or redefining of the lip contour. Patients additionally were required to have the ability and willingness to provide a consent form for the study. Patients were excluded if their lips had been previously treated with a permanent filler or semi-permanent filler (eg, fat, polytetrafluoroethylene, other collagen fillers, acrylic hydrogel/ hyaluronic acid, calcium hydroxylapatite, and/or silicone); had received a touch-up injection of Dermicol-P35 30G less than 4 months prior to the onset of the study; had received an injection of hyaluronic acid or collagen fillers within the previous 12 months; possessed a dermal anomaly in the areas to be injected that may have interfered with the results of the study; had a history of allergies including sensitivity to collagen, local or injectable anesthetic products, any general allergies to certain food or certain chemicals, or a history of multiple severe allergies; or had a serious or chronic disease such as cancer, a history of autoimmune disease, or collagen vascular disease. Patients were additionally excluded if they demonstrated an active skin disease, inflammation, or related condition such as infection, psoriasis, or herpes simplex near the lips or the nasolabial area during injection, or within 6 months prior to injection. Fifty-seven patients were identified who received an injection of Dermicol-P35 30G in the lips 4 to 10 months prior to the onset of the study and were considered for inclusion in the study. Study Assessments Demographics and Injection Characteristics The following data were collected for all patients: demographics (eg, age and race); medical history (eg, known allergies and previous aesthetic treatment; and the treatment details, including the injection site and volume, the type of anesthetic used (if applicable), and the administration of any concurrent therapy during the same session (botulinum toxin or another filler). Efficacy The following efficacy data as listed in Table 1. The subjective impression of overall degree of improvement by the nonblinded clinic investigator: This was assessed at each time point by comparing a pretreatment photograph of the lips to a current photograph of the lips and then rating the impression of the degree of improvement on the following scale: -1=worse than no treatment, 0=no improvement, 1=25% improvement, 2=50% improvement, 3=75% improvement, and 4=100% improvement. A 100% improvement rating denoted the patient had achieved the maximum enhancement of the lips deemed possible by the investigator based on clinical experience. This scale was modeled after the Global Aesthetic Improvement Scale, an established tool to evaluate the subjective efficacy of cosmetic filler substances. 10 The overall satisfaction with the treatment, as evaluated by the clinic investigator who performed the injection: This was assessed in response to the question, Are you satisfied with the results?, using a 4-point scale (very satisfied, satisfied, unsatis-

5 3 fied, or very unsatisfied) immediately after the treatment and at the 4-month to 10-month posttreatment assessment. Table 1. Efficacy and safety posttreatment assessments Safety Data on safety (ie, adverse events [AEs]) were collected immediately following injection with Dermicol-P35 30G and at the assessment conducted 4 months to 10 months postinjection. Swelling, bruising, lumpiness, and pain were assessed by each clinic investigator by physical exam and patient self-report. Swelling, bruising, and lumpiness were evaluated on a subjective 5-point scale (none, very slight, well defined, moderate, or severe), and pain was evaluated on a 4-point scale (none, mild, moderate, or severe). At the visit conducted 4 months to 10 months postinjection, the investigator also evaluated the presence (yes or no) of lip surface irregularity, migration of injected material, nodules, granuloma formation, infection, or patient s change in lip sensation (eg, paresthesia or numbness); further details were requested for any yes answer. results Patient Population A total of 57 patients were identified to have had an injection of Dermicol-P35 30G performed at 1 of the 3 study clinics 4 months to 10 months prior to the onset of the study and were subsequently enrolled. Fifty-one patients met all protocol requirements and were included in the efficacy analyses; 6 patients were not included because they had received a touch-up injection of Dermicol-P35 30G within the 4 months prior to the retrospective time parameters of the study. All 57 patients were included in the safety analyses. surface Migration of injected material The mean patient age was 44.2 years (Table 2). The majority Presence of nodules of patients was female (55/57, 96%) and of Caucasian ancestry. Preexisting allergies were reported by 3 (5%) patients that Granuloma formation included periocular, type Penalties 4 contact allergy; allergy to pollen; Infection Apply and allergy to sulfa drugs. Additional preexisting conditions Change in lip sensation were reported by 4 (7%) patients who had a medical history of facial acne (acne rosacea or acne vulgaris), epilepsy, and maxillofacial reconstruction for problems with dentition. Previous aesthetic treatments were reported by 31 (54%) patients. The majority of these treatments were injection with botulinum toxin in 23 patients (85%, 27 prior treatments). Other facial treatments included hyaluronic acids (eg, Restylane, Hylaform, Perlane ), poly-l-lactic acid (Sculptra ), bovine-derived collagen fillers (Zyderm and Zyplast ), and prior treatment with Dermicol-P35 30G. The mean volume of Dermicol-P35 30G received during visit 2 was 0.8 ml. Twenty-four patients received an additional injection during visit 4; the mean volume was 0.5 ml. The requirements for lip enhancement mostly involved the upper-lip body and the upper-vermilion border. Optimal enhancement was obtained in the majority of patients after the initial injection; only Assessment Efficacy analyses posttreatment Degree of overall improvement (assessed by clinic investigator) Overall satisfaction of clinic investigator Time after injection Immediately after initial injection (and after touch-up injection, if applicable) 4 to 10 months after initial injection Overall satisfaction of patient Safety analyses posttreatment Adverse events Degree of swelling Degree of bruising Degree of lumpiness Degree of pain Presence of irregular lip 42% (24 of 57) of patients requested a touch-up at a subsequent visit. Efficacy Assessments Investigator Assessments Injections of Dermicol-P35 30G into the upper lips and lower lips resulted in improvements in upper-lip and lower-lip volume and contour, which were evident immediately after injection and for several months thereafter (Figure 1). At visit 5 during the retrospective study assessment, most patients (50 of 51 [98%]) were considered to have a degree of improvement in lip enhancement, as assessed using the subjective 6-point rating scale by the investigators who performed the injection (Figure 2). Improvement rated as 50% or better

6 4 Table 1. Patient demographics and exposure to Dermicol-P35 30G (N = 57) Demographic: Gender, n (%) Male Female 2 (4%) 55 (96%) Age (years) Mean (SD) 44.2 (11.2) Known allergies, n (%) No Yes Unknown 45 (79%) 3 (5%) 9 (16%) Preexisting facial conditions No Yes Unknown 47 (82%) 4 (7%) 6 (10%) Figure 1. Injection of Dermicol-P35 30G into the lips: a) 39-year-old female patient with improvement in the contour of the upper and lower lips immediately after injection of 0.7 ml; b) 44-year-old female patient with improvement in upper lip volume (also nasolabial and marionette lines) 2 weeks after injection of 0.5 ml; c) 39-year-old female patient with improvement in upper-lip contour and volume 2 weeks after injection of 0.8 ml of and d) 41-year-old female patient with improvement in upper and lower lip volume and contour 25 weeks after injection of 0.6 ml (upper lip) and 0.4 ml (lower lip). a. Preinjection Postinjection Prior aesthetic treatments to face No Yes Unknown 22 (39%) 31 (54%) 4 (7%) Exposure: Injection site n Mean volume (SD) Visit 2 Total (0.3) Vermilion upper (0.2) b. Vermilion lower (0.2) Lip body (0.2) upper Lip body (0.2) lower Other (0.2) Visit 4 Total (0.2) Vermilion (0.1) upper Vermilion (0.1) lower d. c. Lip body upper Lip body lower (0.2) (0.1) Other (0.1) *57 patients were enrolled and included in the safety analyses; 51 patients were included in the efficacy analyses. was observed in 47 of 51 (92%) patients. Three patients were considered to have 25% improvement and only 1 patient was considered to have no improvement. These results indicated that Dermicol-P35 30G treatments produced decidedly apparent improvement in overall lip conformation and presentation in almost all patients. Investigator Satisfaction At visit 5 during the retrospective study assessment, investigators rated themselves as very satisfied or satisfied with 90% (46 of 51) of the patients lip enhancement (Figure 3). Investigators were unsatisfied with the results from 5 patients (10%). Four of these patients results were unsatisfactory due to the diminishing enhancement effects of Dermicol-P35 30G by the last posttreatment follow-up visit. Only 1 patient assessment

7 5 100% 80% 60% 100% improvement 75% improvement 50% improvement 25% improvement No change Worse 40% 20% 0% Visit 2 Visit 3 Visit 4 Visit 5 Figure 2. Investigator assessment of lip enhancement: The clinic investigator compared the patient s lips to a pretreatment photograph at each visit and subjectively rated the percentage improvement noted. 100% 80% 60% Very satisfied Satisfied Unsatisfied 40% 20% 0% Visit 2 Visit 3 Visit 4 Visit 5 Figure 3. Overall investigator satisfaction with assessment of patient lip enhancement. Clinic investigator satisfaction was subjectively assessed on a 4-point scale.

8 6 100% 80% 60% Very satisfied Satisfied Unsatisfied 40% 20% 0% Visit 2 Visit 3 Visit 4 Visit 5 Figure 4. Overall patient satisfaction with lip enhancement. The degree of patient satisfaction was assessed by questionnaire. During visit 5, the majority of patients were very satisfied or satisfied with their lip enhancement. was deemed unsatisfactory by the clinic investigator due to the presence of a persistent lump on the side of the lip, although the investigator nevertheless considered the lump to be hardly noticeable. Patient Satisfaction During the retrospective study period at visit 5, 94% of patients (48 of 51) considered themselves either very satisfied or satisfied with the Dermicol-P35 30G enhancement results (Figure 4). Of the total patients, 3 patients were unsatisfied (5%), due to the diminishing effects of Dermicol-P35 30G enhancement by the last posttreatment follow-up visit. One of these patients had additionally experienced some persistent lumpiness. Safety Assessments The majority of Dermicol-P35 30G treatments experienced no swelling, bruising, or lumpiness as noted during the short-term and long-term safety assessments (Figure 5). The short-term results of the initial Dermicol-P35 30G treatment revealed that 70% of patients experienced no swelling, 90% experienced no bruising, no patients experienced lumpiness, and only 19% experienced pain. When pain was experienced, it was predominantly due to procedural pain, as the use of local anesthesia was administered only as requested. At the long-term retrospective study visit (visit 5), it was found that 95% of patients experienced no swelling, 100% experienced no bruising, 88% experienced no lumpiness, and 100% experienced no pain associated with Dermicol-P35 30G treatment. Thus, all initial bruising and pain had resolved. When present, lumpiness was assessed as very slight or well-defined, not moderate or severe, and some swelling had also persisted in a few patients. One patient experienced a recurrent herpes infection, and 2 patients experieinced transient changes in lip sensation. conclusion This study was an open, multicenter, retrospective study that evaluated the safety and performance of Dermicol-P35 30G in patients who underwent treatment for lip enhancement up to 10 months prior to the retrospective study period. Results of this study indicated that Dermicol-P35 30G treatments readily produced apparent improvement in overall lip conformation and presentation in ~90% of patients, as assessed by the study investigators at each clinic. Subjective investigator and patient satisfaction with lip conformation and presentation were also over 90%, further solidifying support for a favorable outcomesbased clinical study. Safety was effectively demonstrated by this study. Short-term and long-term safety parameters, including swelling, bruising, lumpiness, pain, irregularities in lip contour, infection, and changes in lip sensation proved to be relatively few. The short-term and long-term AEs, for the most part, did not affect the patient satisfaction with the treatment. Pain was mostly experienced by those patients who did not receive anesthesia. Dermicol-P35 30G has been manufactured to maximally reduce the needle bore down to a 30G needle for injection delivery of the treatment. However, the extent of innervation of the lip and mouth areas makes these areas highly sensitive to any treatment by injection and is decidedly better tolerated with either topical or cutaneous (nerve block) anesthesia. In this study, those patients who received anesthesia

9 7 100% Percent of patients 80% 60% 40% 20% None Very slight/mild Moderate Well defined/severe 0% Swelling Bruising Lumpiness Pain Swelling Bruising Lumpiness Pain Swelling Bruising Lumpiness Pain Swelling Bruising Lumpiness Pain Visit 2 Visit 3 Visit 4 Visit 5 Figure 5. Adverse events of swelling, bruising, lumpiness, and pain reported posttreatment with Dermicol P35 30G. had minimal issues with the route of administration. Furthermore, in this study, pain was shown to not adversely affect patient satisfaction with treatment. Other than pain, AEs associated with the treatment were limited to cosmetic or aesthetic effects; there were no systemic AEs reported. The results of this study support those of a prior investigation with Dermicol-P35 30G for lip augmentation; in a small study of 15 women who received an injection of Dermicol-P35 30G into the lips, cosmetic outcomes were rated as very good by 53% of patients, good by 33%, and satisfactory by 13%. 11 Dermicol-P35 was well tolerated, and most patients experienced only minimal swelling post-injection. One prior study involving a small patient pool had noted the formation of persistent and cosmetically undesirable lip nodules in 80% of patients; 12 this phenomenon had not been noted by other investigators, and no such nodules were noted 4 months to 10 months postinjection in the current study. In addition, the long-term results reported following injection of Dermicol-P35 30G into the lips mirror those of studies following injection into the nasolabial folds. A randomized, multicenter, split-face study comparing the safety and efficacy of Dermicol-P35 and nonanimal-stabilized hyaluronic acid (NASHA) nasolabial fold injections demonstrated persistence of improvement in the modified Fitzpatrick Wrinkle Scale (mfws) scores (defined as an improvement from baseline of at least 0.5 points) in 99% and 97% of patients at 3 and 6 months, respectively. Seventy-two percent of patients were rated by investigators in the highest improvement category (much better) on a 4-point scale at 6 months following Dermicol-P35 30G injection; 50% of patients rated their improvement similarly. 13 In another randomized, multicenter, 12-month study comparing Dermicol-P35 30G with a hyaluronic acid filler for correction of nasolabial folds, a high percentage of patients had persistent mfws scores at 9 months and 12 months postinjection (95% and 77%, respectively); in addition, the aesthetic appearance of the nasolabial folds were rated by a blinded investigator as better or much better on a 4-point scale in 97% and 87% of patients, respectively, at 9 and 12 months. 14 In conclusion, these retrospective study results support Dermicol-P35 30G treatment as a safe and effective treatment. disclosures ColBar LifeScience Ltd. was the sponsor of this study. AcknowledgeMent The manuscript was prepared with assistance from Thomson Reuters. 1. references 2. American Society of Facial Plastic and Reconstructive Surgeons (AAF- PRS) Membership Survey: Trends in Facial Plastic Surgery. Alexandria, VA: American Society of Facial Plastic and Reconstructive Surgeons, De Boulle K. Management of complications after implantation of fillers. J Cosmet Dermatol. 2004;3: Klein AW. Collagen substances. Facial Plast Surg Clin North Am. 2001;9:

10 DeLustro F, Smith ST, Sundsmo J, et al. Reaction to injectable colla- gen: results in animal models and clinical use. Plast Reconstr Surg. 1987;79: Hanke CW, Coleman WP III. Dermal filler substances. In Asken S, Alt TH, Hanke CW, Coleman WP III, eds. Cosmetic Surgery of the Skin. St Louis: Mosby, 1997: Tanaka S, Avigad G, Eikenberry EF, et al. Isolation and partial charac- terization of collagen chains dimerized by sugar-derived cross-links. J Biol Chem. 1988;263: Pitaru S, Noff M, Block L, et al. Long-term efficacy of a novel ribose- cross-linked collagen dermal filler: a histologic and histomorphometric study in an animal study. Dermatol Surg. 2007;33: Monstrey SJ, Pitaru S, Hamdi M, et al. A two-stage phase I trial of Evolence30 collagen for soft-tissue contour correction. Plast Reconstr Surg. 2007;120: Shoshani D, Markovitz E, Cohen Y, et al. Skin test hypersensitivity study of a cross-linked, porcine collagen implant for aesthetic surgery. Dermatol Surg. 2007;33:S152-S158. Narins RS, Brandt F, Leyden J, et al. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003;29(6): Landau M. Lip augmentation and rejuvenation using a novel por- cine collagen-derived filler. J Drugs Dermatol. 2008;7: Braun M, Braun S. Nodule formation following lip augmentation using porcine collagen-derived filler. J Drugs Dermatol. 2008;7: Narins RS, Brandt FS, Lorenc ZP, et al. A randomized, multicenter Address for correspondence Koen De Boulle MD Aalst Dermatology 43 Leopoldlaan, Aalst 9300 Belgium Phone:... (32) koendeboulle@pandora.be study of the safety and efficacy of Dermicol-P35 and non-animal stabilized hyaluronic acid gel for the correction of nasolabial folds. Dermatol Surg. 2007;33:S213-S221. Narins RS, Brandt FS, Lorenc ZP, et al. Twelve-month persistency of a novel ribose-cross-linked collagen dermal filler. Dermatol Surg. 2008;34:S31-S39.

11 This supplement to the Journal of Drugs in Dermatology is supported by a medical education grant from

12 JDD