Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
  • A61K2800/91—Injection

Definitions

• the present disclosure provides a method for maintaining and/or prolonging injectable filler composition efficacy. This can be especially relevant to increase the aesthetic benefit of implanted materials.
• the present disclosure provides a method of injecting an injectable filler such as hyaluronic acid (HA) so that it provides longer lasting, superior, or longer lasting and superior benefits.
• an injectable filler such as hyaluronic acid (HA)
• these benefits can include improved volume and/or firmness to a subject ' s skin.
• the invention comprises a method for providing an injectable filler composition to a subject for cosmetic purposes.
• the method can comprise performing an initial treatment session on a subject that comprises a first injection of a first injectable filler composition into the subject at a target area, thereby providing an increase in volume and/or firmness to the target area.
• the method can further comprise performing a re- treatment session on the subject.
• the re-treatment session can comprise a second injection of a second injectable filler composition into the target area at a time subsequent to the initial treatment session.
• the second injection extends the increase in volume and/or firmness of the target area.
• the time subsequent to the initial treatment session is in the range of 1 month to less than 9 months, and at least one of the first or second injectable filler compositions comprises hyaluronic acid.
• the invention comprises a method for providing a target area of a subject with a continuing increase in firmness and/or volume following a re- treatment session of an injectable filler composition.
• the method can comprise identifying a subject that will benefit from a continuing increase in a volume and/or firmness of a target area during a period following a re-treatment session and continuing for at least 13 months after the re-treatment session.
• the volume and/or firmness can increase throughout this period.
• the method can further comprise performing an initial treatment session on the subject.
• the initial treatment session can comprise a first injection of a nonanimal stabilized hyaluronic acid and thereby provide an increase in volume and/or firmness to the target area.
• the method can further comprise performing a re-treatment session on the subject.
• the re- treatment session can comprise a second injection of the nonanimal stabilized hyaluronic acid into the target area at a time subsequent to the initial treatment session.
• the subject's global aesthetic improvement scale can continue to improve for at least 10.5 months following the re-treatment session.
• the re-treatment session can occur 2 to 6 months after the initial treatment session.
• the subject can maintain at least a 1 point improvement in a global aesthetic improvement scale score and/or a wrinkle severity rating score for 18 months after the initial treatment session, hi some embodiments, the subject receives no additional injections of said nonanimal stabilized hyaluronic acid to the target area, except for the initial treatment session and the re-treatment session.
• the invention comprises a kit for providing a continuing increase in firmness and/or volume from an injectable filler composition.
• the kit can comprise a dermal filler, a syringe, a needle, and instructions to 1) perform an initial treatment session on a subject.
• the initial treatment session comprises a first injection of a first injectable filler composition into the subject at a target area, which provides an increase in volume and/or firmness to the target area.
• the instructions further instruct one to 2) perform a re-treatment session on the subject.
• the re-treatment session comprises a second injection of a second injectable filler composition into the target area at a time subsequent to the initial treatment session.
• the second injection extends the increase in volume and/or firmness of the target area.
• the time subsequent to the initial treatment session is in the range of 1 month to less than 9 months.
• At least one of the first or second injectable filler compositions comprises hyaluronic acid.
• FIG. 1 is a schematic depicting a protocol for a study involving comparison of a re-treatment session after 4.5 months with re-treatment session after 9 months.
• FIG. 2 is a table outlining the schedule of procedures for a trial study involving comparison of a re-treatment session after 4.5 months with re-treatment session after 9 months.
• FIG. 3 is a bar graph summarizing results from a trial study.
• the bar graph shows a comparison of the percent of responders that received a re-treatment session at 4.5 months to the percent of responders that received a re-treatment session after 9 months.
• FIG. 4 is a line graph summarizing results from a trial study.
• the line graph shows a comparison of the improvement resulting from re-treatment at 4.5 months with re-treatment after 9 months at the indicated time points.
• FIG. 5 is a line graph summarizing results from a trial study.
• the line graph shows a comparison of wrinkle severity from re-treatment at 4.5 months with re- treatment after 9 months at the indicated time points.
• FIG. 6 is a line graph summarizing results from a trial study.
• the line graph shows a comparison of the improvement resulting from re-treatment at 4.5 months with re-treatment after 9 months at the indicated time points.
• the data used to prepare the curves represents the completers subset of the data.
• FIG. 7 is a line graph summarizing results from a trial study.
• the line graph shows a comparison of the improvement resulting from re-treatment at 4.5 months with re-treatment after 9 months at the indicated time points.
• the zero time in the graph represents the time immediately following the re-treatment time.
• FIG. 8 is a graph depicting the percent of subjects with at least one grade of improvement from baseline by visit for the 4.5 month re-treatment.
• FIG. 9 is a graph depicting the percent of subjects with at least one grade of improvement from baseline by visit for the 9 month re-treatment.
• FIG. 10 is a graph depicting the mean improvement from baseline by visit for the WSRS results for the re-treatment at 4.5 months.
• FIG. 11 is a graph depicting the mean improvement from baseline by visit for the WSRS results for the re-treatment at 9 months.
• the degree or extent of the improvement itself, at various time points following the re-treatment is also improved over what would ordinarily be expected from two unrelated administrations of a dermal filler; thus, not only is the duration of the benefit extended, but the degree or extent of the benefit itself is also improved.
• the timing of the re- treatment session can allow one to maintain more of the benefits from the injectable filler throughout a continuous period, without losing some of the benefits of the initial treatment session.
• the actual amount of dermal filler required to obtain the above surprising and superior results is surprisingly less than the amount required for two traditional treatment sessions.
• the method provide a synergistically long lasting and unexpectedly high level of volume and/or firmness throughout the longer period of time, but such results are achieved with substantially less dermal filler than would be expected for two separate administrations.
• not all of the embodiments will exhibit all of these superior and unexpected results; however, many of the embodiments can exhibit more than one of the above noted surprising and superior results.
• the methods described herein involve applying an injectable filler to correct areas or locations that appear to lack volume or are "under volume,” and, at a subsequent time (as a separate treatment session), re-treating the area with the injectable filler composition.
• this retreatment session will occur within a specific time period and/or before the subject might otherwise believe that they would benefit from an additional administration of the injectable filler composition ⁇ absent the information provided in the present disclosure), hi some embodiments, the re-treatment session is provided within or less than 9 months from the initial treatment session.
• At least one of the sessions will involve an injectable filler composition that can induce or stimulate collagen production (such as a hyaluronic acid-containing composition).
• an injectable filler composition that can induce or stimulate collagen production (such as a hyaluronic acid-containing composition).
• re- treatment can slow the rate of resorbtion of the injectable filler after re-treatment.
• re-treatment can slow the rate of resorbtion of the injectable filler after re- treatment by maintaining tissue expansile tension.
• the re- treatment procedure can provide results lasting for at least 13.5 months if not longer. In some embodiments, little or no loss of volume is observed after about 18 months after initial treatment.
• re-treatment can be performed, for example, prior to the occurrence of an unfavorable change in wrinkle severity in the treated area.
• One advantage of such an embodiment is that a substantial increase to a subject's baseline wrinkle severity can be avoided throughout a longer duration of time.
• the timing of the re- treatment schedule can be such that one can reduce decreases or losses in a first treatment's effectiveness, while still providing for a second treatment (the "re-treatment") in a sufficient period of time to allow for the enhanced duration of effectiveness of the treatment.
• re-treatment provides continued improvement of volume and/or firmness.
• the improvement is continuous over a period of time up to about, for example, 13 or 14 months after re-treatment.
• the improvement is due at least in part to the stimulation of collagenesis.
• re- treatment can increase collagen production by fibroblasts.
• injectable filler composition and "injectable filler' are used in their ordinary sense as understood by those skilled in the art and thus include a composition that can be administered through injection into or beneath the skin of a subject.
• the injectable filler composition should not be unduly problematic for the subject receiving the composition.
• the fillers are dermal fillers.
• the filler is selected from RESTYLANE® and PERLANE® dermal fillers. Examples of fillers include those disclosed in U.S. Pat. Nos.
• the composition is a cross-linked biocompatible polysaccharide gel composition.
• the composition is formed by forming an aqueous solution of a water soluble, cross-linkable polysaccharide; initiating a cross-linking of said polysaccharide in the presence of a polyfunctional cross-linking agent; sterically hindering the cross-linking reaction from being terminating before gelation occurs, an activated polysaccharide thereby being obtained; and reintroducing sterically unhindered conditions for said activated polysaccharide so as to continue the cross-linking thereof up to a viscoleastic gel.
• the injectable filler is characterized by its source.
• the source can be biologic and/or synthetic.
• Biologic injectable fillers can be those that are derived from a living organism. Synthetic injectable fillers can further be divided into two groups, a) man-made fillers for which there is no biologic counterpart and b) man-made substances for which there is a counterpart biologic.
• the injectable filler can be characterized by the body's ability to clear a product without external intervention (e.g., these can be biodegradable or nonbiodegradable).
• biologic, biodegradable fillers are those that include materials derived from organism, human, and/or animal tissues and/or products.
• examples of such fillers include the following: hyaluronic acid, (such as the following: avian HA, bovine HA, and non-animal stabilized HA ("NASHA", e.g., RESTYLANE® injectable filler)), collagen (such as collagen I, collagen II, collagen 111, cross-linked and/or noncross-1 inked, bovine, porcine, human, and autologous collagen).
• collagen based fillers include ZYPLAST® (collagen derived from bovine tissue), ZYDERM® I (collagen derived from bovine tissue), ZYDERM® II, (collagen derived from bovine tissue), EVOLENCETM (porcine derived collagen), and F1BRELTM (porcine derived collagen).
• the injectable filler is self-replicating, and can include living cells (such as collagen-producing cells or fibroblasts).
• Synthetic, biodegradable, injectable fillers include RADIANCETM and RADIESSETM (microspheres of at least calcium and phosphate ions) injectable fillers, polyacids and polyethers described in U.S. Pat. No. 7,192,984 (e.g., carboxymethyl cellulose (CMC) and polyethylene oxide), and LARESSE® (polymer, polyacid, and /or polyether, similar but not identical to HA type materials).
• RADIANCETM and RADIESSETM microspheres of at least calcium and phosphate ions injectable fillers
• polyacids and polyethers described in U.S. Pat. No. 7,192,984 e.g., carboxymethyl cellulose (CMC) and polyethylene oxide
• LARESSE® polymer, polyacid, and /or polyether, similar but not identical to HA type materials.
• Synthetic, non-biodegradable, injectable fillers include injectable fillers that are not readily broken down in the body.
• Synthetic, non-biodegradable, injectable fillers can include injectable fillers that include a biologic component (and vice versa). In some embodiments, at least a portion of product cannot be significantly broken down by various body processes.
• synthetic non-biodegradable fillers include the following: ARTEFILTM (polymethylmethacrylate (PMMA) microspheres suspended in bovine collagen), ARTECOLTM (polymethylmethacrylate (PMMA) microspheres suspended in bovine collagen), polymethylmethacrylate (Plexiglas) in bovine collagen carrier, denatured, silicone, and various polymers, polyacids, and polyethers.
• the carrier has rapid biodegradation.
• any one, combination, or ingredient of the above fillers can be combined with the other fillers (or alternative fillers) in various embodiments and for particular results.
• injectable fillers need not be categorized by both their source and their ability to stay or be cleared from the body. That is, some fillers can simply be biological, synthetic, biodegradable, or nonbiodegradable. Additionally, as can be appreciated by one of skill in the art, some injectable fillers can include parts or aspects of various combinations of the above or following substances.
• injectable fillers include a substance selected from the following: collagen, fat, human or animal derived collagen, bovine collagen, type 1 collagen, type II collagen, type III collagen, 3.5% bovine dermal collagen cross-linked by glutaraldehyde to form a latticework, natural human collagen, autologous collagen, polymethylmethacrylate microspheres (optionally suspended in bovine collagen), suspension of collagen fibers prepared from the subject's tissue, human tissue collagen matrix derived from cadaveric dermis, the polyacids and polyethers described in U.S. Pat. No.
• 7,192,984 e.g., carboxymethyl cellulose (CMC) and polyethylene oxide
• CMC carboxymethyl cellulose
• acellular human cadaveric dermis that has been freeze-dried micronized acellular human cadaveric dermis that has been freeze-dried, cultured autologous fibroblasts, hyaluronic acid, non-animal-stabiJized hyaluronic acid derivative, microspheres of calcium hydroxy!
• appetite suspended in an aqueous gel carrier dextran beads suspended in hylan gel of nonanimal origin (e.g., 40- to 60- ⁇ m in diameter), solubilized elastin peptides with bovine collagen, silicone, solubilized elastin peptides with bovine collagen, poly-L-lactic acid, Gore-Tex (PTFE), glycosylated collagen, PMMA, bone-forming calcium apatite, cultured human cells, expanded polytetrafluoroethylene (e-PTFE), SOFTFORM® of ePTFE, and some combination thereof.
• hylan gel of nonanimal origin e.g. 40- to 60- ⁇ m in diameter
• solubilized elastin peptides with bovine collagen silicone
• solubilized elastin peptides with bovine collagen poly-L-lactic acid
• Gore-Tex PTFE
• glycosylated collagen PMMA
• PMMA bone-forming calcium apatite
• injectable fillers include the following: AQU AMID® (comprising water and cross-linked polymers), ARTEFIL® (polymethylmethacrylate (PMMA) microspheres suspended in bovine collagen), LARESSE® Dermal Filler (synthetic, biocompatible polymers, non-HA gel comprising absorbable medical polymers), ARTECOLL® (polymethylmethacrylate (PMMA) microspheres suspended in bovine collagen).
• BIO-ALCAMIDTM synthetic reticulate polymer (poly-alkyl-imide), CAPTIQUETM (non-animal hyaluronic acid), COSMODERMTM (human collagen skin filler), COMOPLASTTM, CYMETRA®, autologen, DERMALOGEN®, FASC ⁇ ANTM (fascia), fascia, fat, hylaformTM (avian hyaluronic acid), JUVEDERM® (biosynthesized, non-animal hyaluronic acid), RADIESSETM (microspheres of at least calcium and phosphate ions), SCULPTRA® (poly-L-lactic acid (PLLA)), collagen, hyaluronic acid, RESTYLANE®, PERLANE®, ZYDERM®, ZYPLAST® (collagen derived from bovine tissue), DERMALIVE®, (hyaluronic acid and acrylic hydrogel particles), DERMADEEP® (synthetic reticulate poly
• any of the above fillers or components thereof can include other materials, for example, anesthetic materials, including, without limitation, lidocaine, prilocaine, tetracaine, etc.
• volumetric filler is a type of injectable filler composition.
• Volumetric fillers can be dermal fillers.
• the volumetric filler is capable of crosslinking and/or is cross-linked.
• Cross-linked compositions allow the filler to have predictably no or minimal volume or substance loss on injection. In some embodiments they also provide predictable expansion or "swelling" with re-hydration on injection: swelling to no more than 10% volume increase; not “shrinking" or losing volume as some fillers that lose water uncross-linked HA volumes; and/or have sufficient tensile compression resistance.
• the volumetric filler involves microbead technology (e.g., as disclosed in U.S.
• Patent Numbers 5,633,001 and 5,007,040, herein incorporated by reference in their entireties this allows compression resistance. In some embodiments this allows for the composition to have the ability to resist displacement.
• Other fillers, described as "slurries,” can be used but can be prone to displacement (e.g., disclosed in U.S. Patent Nos. 5,143,724, 5,633,001, herein incorporated by reference in their entireties).
• the filler has the biocompatibility and "feef of tissue rather than boney implants or sedimentary products that can feel hard.
• bony implant or sedimentary fillers can also be used in some embodiments,
• Demal filler is a type of injectable filler composition. Dermal filler denotes that the filler is compatible for use in or under the skin. Dermal fillers can be volumetric fillers, hi some embodiments, the dermal filler composition comprises, consists, or consists essentially of a hyaluronic acid or hyaluronic acid derivative. The te ⁇ n "hyaluronic acid” includes salts and bases thereof. In some embodiments, the hyaluronic acid comprises a nonanimal stabilized hyaluronic acid, including gels thereof.
• the hyaluronic acid comprises avian HA, bovine HA, or human HA (e.g., RESTYLANE® and PERLANE® injectable fillers)).
• the hyaluronic acid comprises at least one of CAPTIQUETM (non-animal hyaluronic acid), HYLAFORMTM (avian hyaluronic acid), JUVEDERM® (biosynthesized, non-animal hyaluronic acid), DERMALIVE®, (hyaluronic acid and acrylic hydrogel particles), DERMADEEP® (hyaluronic acid and acrylic hydrogel particles), HYDRAFILL®, PURAGENTM (filler comprising double cross-linked hyaluron molecules), and/or REVIDERM® INTRA (filler comprising flexible DEXTRAN micro-beads suspended in super-coiled, stabilized hyaluronic acid).
• extend in reference to an improvement of firmness and/or volume denotes that the duration, degree, or duration and degree of the improvement has been increased or "extended”.
• extend can refer to an extension in the amount of time that the improvement is present, and the term “extend” can also denote that the size of the improvement, either overall or at a specific point in time, has also increased.
• the term can denote both of these aspects at once as well.
• the term "improvement" in reference to firmness and/or volume denotes that there has been an increase in the apparent firmness of a subject's skin that has received the injectable filler and/or that there has been an apparent increase in the volume of an under volume area.
• An increase in volume would include the removal or diminution of lines, wrinkles, and/or undervolume areas in the subject's skin.
• an improvement in firmness and/or volume can be described by using the Wrinkle Severity Rating Scale ("WSRS"). Values can be assigned as follows: 1 -Absent, 2- MiId, 3-Moderate, 4-Severe, and 5-Extreme.
• a decrease in the WSRS can denote an improvement in volume and/or firmness.
• an improvement in firmness and/or volume can be described by the Global Aesthetic Improvement Scale ("GAlS' * ), which can have values assigned as follows: 0 - Worse; 1 - No Change; 2 - Improved; 3 - Much Improved; and 4 - Very Much Improved.
• GAS' * Global Aesthetic Improvement Scale
• changes in volume and/or firmness can be characterized simply as a change in volume and/or firmness, without using either the WSRS or the GAIS. The skilled in the art will appreciate that the determination of a WSRS or GAIS score is made by a trained evaluator.
• the methods described herein are used to alter the appearance of a subject's face.
• this alteration is purely an aesthetic alteration
• the alteration does not treat or adjust any deformity that the subject may have.
• the subject may simply want added volume to various areas of their face.
• the application of filler will not necessarily be considered a treatment of the subject's face in all embodiments.
• the term "under volume'" does not imply or require that there is necessarily a deformity in the subject's face. Rather, it simply denotes that there appears to be less volume under the skin in one area than in another.
• the filler and technique is applied as a treatment of a deformity in a patient.
• Such applications can be more specifically denoted by the recitation of the fact that a "deformity' is being "treated,” or by the fact that the subject is called a "patient.”
• Applications in which no deformity is being addressed can be more specifically denoted by the use of the terms "non-treatment,” “subject-preference” or similar term.
• the techniques and aspects are generic to both treatment and non-treatment applications.
• the tenn "subject” encompasses "patient.”
• the method is used to reduce or reverse the signs of aging.
• Target area refers to areas or locations to be treated with injectable filler composition, and includes areas or locations that appear to lack volume or are “under volume.”
• “Target areas” include locations of, for example, oral commissures, marionette lines, mandibular hollows, raise jowls, frowning mouth, pouty lower lip, lateral expression lines, mental creases, chin dimplings, zygomatic hollows, nasolabial folds, tear troughs, malar area or prominence, and brow lifts.
• treatment can denote a purely cosmetic result and one that can remove or reduce signs of aging.
• the term "initial treatment ' " or "initial treatment session” denotes the application of an injectable filler to a location that does not currently retain a significant amount of an exogenous injectable filler.
• an initial treatment can be performed to achieve a "full correction" of a location.
• this initial treatment can include a "touch-up” application, approximately one to two weeks after the initial injection session.
• the touch-up application is a step that is done as part of the initial treatment session and performed to bring the subject's appearance into full correction.
• the term "initial treatment” will include both the initial injection(s) ⁇ or the "initial injection session") and, if needed, a subsequent injection (or set thereof) described as a "touch-up" application or injection.
• the touch-up application is designed to bring the treated area into full correction.
• a touch-up application generally involves the application of a smaller amount of a dermal filler compared to the initial injections of the dermal filler.
• the volume of dermal filler applied during the initial injection session is more than 0.5 cc per side of a subject's face, for example, 0.5- 0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, 0.9-1, 1-1.1, 1.1-1.2 cc or more (e.g., 1-2, 2-3, 3-4, 4-5 cc, or more).
• the volume of dermal filler applied during the touch-up application is generally less, e.g., approximately 0.2 to 0.3, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7 cc (for each side of a subject ' s face).
• ITS initial treatment session
• the ITS will be described as occurring as of the initial injection session, even if there is a touch-up application two weeks later.
• a re-treatment occurs 4.5 months after an ITS, it is the initial injection session that occurred 4.5 months before the re-treatment session, and if any touch-up application occurred, it could have happened 4 months prior to the re- treatment session (assuming the touch-up application occurred two weeks after the initial injection session).
• re-treatment or "second treatment " session denotes an application of an injectable filler that is distinct from the initial treatment session (e.g., the initial injection session and, optionally, the touch-up application) and occurs following a full- correction of the location that the injectable filler is applied to.
• the re-treatment occurs after the full correction has been achieved and is performed prior to the complete degradation of the product from the initial treatment. In some embodiments, the re-treatment is applied two months after the initial treatment. In some embodiments, the re-treatment occurs following the degradation of the dermal filler from the initial treatment. In some embodiments, the re- treatment occurs after any touch-up application and thus can be more than 0.5 months after the initial injection session.
• re-treatment session occurs 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12 or more months following the initial treatment.
• the re-treatment occurs following the initial treatment, but after the volume of the dermal filler that was applied to the subject has decreased, thereby allowing additional dermal filler to be added to the subject. While the volume can vary, the average volume applied for the re-treatment can be 0.3 cc or greater, for example. 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.9-1, 1-1.1 cc or greater, for each side of a subject's face.
• the "re-treatment” can occur after any number of previous initial treatments or re-treatments.
• a subject undergoes more than one re-treatment (each appropriately timed with respect to one another).
• the subject undergoes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more re- treatment sessions.
• the previous "re-treatment " is considered to be an "initial treatment session" as far as the timing of the applications is concerned.
• a subject can receive an initial treatment session at time zero, a first re-treatment at 4.5 months, and then an additional retreatment session at any point more than one month after the first re- treatment session.
• the re-treatment only occurs after the very first treatment session, and any subsequent application of the methods described herein will commence after the subject's appearance has returned to its initial (pre- initial treatment session) volume and/or firmness.
• the "touch-up" application is distinct from a second or re-treatment session.
• the touch-up application is used in order to first achieve a desired result and typically occurs within one or two weeks of the initial injection.
• the touch up application is not used to extend an effect of HA, nor do those skilled in the art characterize it as such, as a touch-up application is used to achieve the desired result in the first place ⁇ e.g., a full correction).
• the re- treatment session occurs after the time period that a touch-up application would occur and results in an extended improvement of the effects of HA (which can be part of the initial treatment session, the re-treatment session, or both sessions).
• a re- treatment session will occur after the subject has received a full correction.
• the volume of the dermal filler for the initial injection session is greater than the volume used in the re-treatment session, which is greater than the optional volume used in the touch-up application.
• a "full correction” denotes that the volume desired has been achieved in the subject's skin due to the presence of the dermal filler ⁇ e.g., excluding swelling from the application of the dermal fillers).
• the present disclosure demonstrates that, rather than waiting to begin a completely new round of treatment, there are significant advantages to using an appropriately timed treatment regime.
• Such "re-treatmenf : methods can result in surprisingly effective extended effects, with subjects retaining high levels of improvements in volume and/or firmness for 9, 10, 11, 12, 13 months and longer.
• early re- treatment can be superior as patients can reduce any increase in wrinkle severity before receiving a second treatment.
• the amount of injectable filler employed in the re-treatment session can be surprisingly low, in order to achieve the above noted surprising and superior results.
• the method includes an initial treatment session, followed by a re-treatment session within less than 9 months of the initial treatment session. In some embodiments, for even greater surprising and superior results, the re-treatment session occurs within less than 6 months from the initial treatment session. While different injectable fillers can be used for the two different sessions, in an embodiment at least one of the sessions (and optimally both) will include hyaluronic acid (e.g., a NASHA) as the injectable filler.
• hyaluronic acid e.g., a NASHA
• the presently disclosed re-treatment method is not merely providing a second round of a previous treatment, but in some embodiments, provides numerous surprising and unexpected advantages by a mechanism that appears to be fundamentally different from the mechanism underlying the current single treatment session.
• Some of the disclosed embodiments are useful for maintaining, prolonging, extending, and/or improving the results of treatment with injectable fillers.
• methods involve, for example: treating, with injectable filler, areas that appear to be "under volume" in a subject; optionally touching-up any areas as needed within, for example, one to two weeks of the initial treatment; and re-treating the subject with injectable filler at an appropriate interval following the initial treatment session.
• Such a method can greatly extend the duration of benefit obtained from an injectable filler.
• the use of a re-treatment step allows for the benefits to be extended for more than 6, 7, 8, 9, 10, 11, 12, 13 months or more.
• at least one of the treatment sessions will include an injectable filler that includes HA. In some embodiments, both sessions will include HA.
• the re-treatment session can occur relatively close in time to the initial treatment session so that subjects do not experience an increase in wrinkle severity before receiving the re-treatment, which can still allow for the prolonged benefits of the dual treatment method described herein.
• the dual session treatment process is believed to maintain tissue expansile tension and slow gel resorption so that benefits and duration of effectiveness of the injections can be extended (and appear the same when comparing re-treatment durations of 4.5 months and 9 months, as described in the examples).
• a subject can be treated with injectable filler to correct areas or locations that appear to lack volume or are "under volume, " and, at a subsequent time, the same areas or locations can be re-treated with injectable filler.
• a third, fourth, fifth, or additional treatments with injectable filler can be performed.
• a time course of treatments can be determined, for example, by evaluation of treatment outcome at various time points. The evaluation can be performed during, for example, follow-up sessions.
• the injectable fillers used can be any injectable filler suitable for correcting areas or location that appear to lack volume. Examples of injectable fillers are provided in the previous section and include, for example without limitation, volumetric fillers and dermal fillers.
• the injectable filler can be, for example, RESTYLANE® de ⁇ nal filler.
• the injectable filler used for the initial treatment can be the same as the injectable filler used for re-treatment. For at least one of the treatment sessions in some embodiments, at least one of the injectable fillers will stimulate collagen synthesis.
• This filler can comprise, for example, HA.
• the injectable fillers used for the initial treatment and re-treatment are different. In cases where the injectable fillers used to re-treat is different from the injectable filler used for the initial treatment, the injectable fillers used to re-treat can improve the efficacy of the injectable filler used for the initial treatment.
• the injectable filler comprises a substance such as hyaluronic acid.
• the initial treatment and the re- treatment employ a same or similar susbstance as the injectable filler.
• the initial treatment employs a HA substance and the re-treatment employs any injectable filler.
• the initial treatment employs any injectable filler and the re-treatment employs an HA substance, hi some embodiments, the HA is 100,000 gel particles/ml filler.
• the initial treatment and re-treatment employ injectable fillers that do not include HA.
• the filler for the initial injection session and the touch-up application are the same type of injectable filler.
• the injectable filler for the initial injection session and the touch-up application are different types of injectable fillers.
• the touch-up dermal filler is HA.
• the filler for the initial treatment allows for expansion of the tissue while also being capable of being absorbed into the skin or degraded.
• the hyaluronic acid is generated by a Streptococcus species of bacteria, hi some embodiments, the hyaluronic acid is stabilized , e.g., non-animal stabilized.
• the hyaluronic acid is chemically crosslinked with BDDE ⁇ 1 ,4 butanediol diglycidyl ether), stabilized (e.g., NASHA), and suspended in phosphate buffered saline at a pH of 7 and a concentration of 20 mg/ml.
• the hyaluronic acid is free of animal protein.
• the hyaluronic acid is a gel generated by a Streptococcus species of bacteria, chemically cross-linked with BDDE, stabilized, and suspended in saline at pH 7 ⁇ e.g., as in RESTYLANE® dermal filler, RESTYLANE TOUCHTM dermal filler, RESTYLANE FINE LINESTM dermal filler, RESTYLANE VITALTM dermal filler, and RESTYLANE LIPPTM dermal filler).
• RESTYLANE® dermal filler RESTYLANE TOUCHTM dermal filler
• RESTYLANE FINE LINESTM dermal filler RESTYLANE VITALTM dermal filler
• LIPPTM dermal filler RESTYLANE LIPPTM dermal filler
• the hyaluronic acid is one that is suitable for injection into a dermal location where it acts to stimulate collagen synthesis.
• the hyaluronic acid is in the form of gel particles.
• the hyaluronic acid is in the form of gel particles having sizes in the range of about 940 microns to about 1090 microns.
• the largest fraction of gel particles size is between 940 microns and 1090 microns (e.g., as in PERLANE® dermal filler).
• the hyaluronic acid gel particles have a particle size that is less than 1200 microns. In some embodiments, the hyaluronic acid gel particles have a particle size that is about 400 microns.
• the hyaluronic acid gel particles have a particle size that is less than 400 microns. In some embodiments, the hyaluronic acid gel particles have a particle size that is more than 400 microns. In some embodiments, the hyaluronic acid gel particles have a particle size that is in the range of about 400 to about 1200 microns.
• the concentration of hyaluronic acid gel particles in the dermal filler may vary over a broad range, e.g., about 500-200,000 particles per mL, such as about 500-5000 particles per ml, about 5,000-50,000 particles per ml, about 50,000-150,000 particles per ml, or about 150,000-200,000 particles per ml.
• the dermal filler comprises about 200,000 hyaluronic acid gel particles per ml (e.g., as in RESTYLANE FINE LINESTM dermal filler and RESTYLANE TOUCHTM dermal filler), ⁇ n some embodiments, the dermal filler comprises about 100,000 hyaluronic acid gel particles per ml (e.g., as in RESTYLANE ⁇ dermal filler). In some embodiments, the dermal filler comprises about 10,000 hyaluronic acid gel particles per ml ⁇ e.g., as in PERLANE® dermal filler).
• the dermal filler comprises about 1 ,000 hyaluronic acid gel particles per ml (e.g., as in RESTYLANE SUBQ 1 M dermal filler).
• the package inserts for RESTYLANE® dermal filler and PERLANE® dermal filler are hereby incorporated by reference in their entireties, and particularly for the purpose of describing those brands of dermal filler products.
• the hyaluronic acid composition comprises a cross- linked biocompatible polysaccharide gel composition, which is obtainable by cross-linking a cross-linkable polysaccharide with a polyfunctional cross-linking agent in two steps, the first cross-linking step can be terminated before gelation occurs by a sterical hindrance of the cross-linking reaction.
• the second cross-linking step can be initiated by reintroducing sterically unhindered conditions for the cross-linking reaction. This reaction can continue up to a viscoelastic gel, wherein the gel composition exhibits retained biocompatibility, viscoelasticity and does not swell substantially when placed in contact with water.
• the stabilized hyaluronic acid composition is that disclosed in U.S. Pat. No. 5,827,937, hereby incorporated by reference in its entirety and particularly for the purpose of describing hyaluronic acid compositions and methods of making them.
• the stabilized hyaluronic acid can be prepared as described in U.S. Pat. No. 5,827,937.
• this process can include the following steps: forming an aqueous solution of a water soluble, cross-linkable polysaccharide; initiating a cross-linking of said polysaccharide in the presence of a polyfunctional cross-linking agent therefor; sterically hindering the cross-linking reaction from being terminated before gelation occurs (thereby obtaining an activated polysaccharide); and reintroducing sterically unhindered conditions for said activated polysaccharide so as to continue the cross-linking thereof.
• the process involves a cross-linking of a water-soluble, cross-linkable polysaccharide in at least two steps or stages, where the cross-linking reaction is discontinued before the galation is initiated.
• the discontinuance can be accomplished by sterically hindering the cross-linking reaction.
• the cross-linking reaction can then be continued in a second step by reintroducing sterically unhindered conditions.
• Any known cross-linking agent can be used, if it is useful in connection with polysaccharides, consideration being taken to ensure that the biocompatibility prerequisites are fulfilled.
• the cross-linking agent is selected from the group consisting of aldehydes, epoxides, polyaziridyl compounds, glycidyl ethers and dividylsulfones.
• glycidyl ethers represent an especially preferred group, of which 1 ,4-butandioI digylcidylether can be referred to as a preferred example.
• the initial cross-linking reaction in the presence of a polyfunctional cross-linking agent can be performed at varying pH values, primarily depending on whether ether or ester reactions should be promoted.
• this means that said cross-linking reaction is performed at an alkaline pH, especially above pH 9, e.g.
• the activation of the polymer can occur under alkaline conditions and as follows: 10 g of hyaluronic acid from Streptococcus can be dissolved in 100 ml of 1% NaOH pH > 9.
• Cross-linking agent in the form of 1 ,4-butandiol diglycidylether can be added to a concentration of 0.2%. The solution can be incubated at 40 degrees Celsius for 4 hours.
• the activation of the polymer can occur under acidic conditions and as follows: similar as above, but at an acidic pH of about 2-6 by the addition of 1% of acetic acid to the solution instead of NaOH.
• Some of the indications which can be addressed by the systems and methods disclosed herein include: oral commissure, marionette lines, mandibular hollow, raise jowl, frowning mouth, pout lower lip, later expression lines, mental crease, chin dimpling, zygomatic hollow, nasolabial folds, tear trough, and brow lift.
• the objective of the initial treatment can be to achieve a desired cosmetic result at the areas of treatment.
• defects i.e., areas or locations that appear to lack volume or are "under volume"
• the amount of correction maybe ascertained by visual assessment of appearance of the defect.
• the amount of correction can be determined with the aid of, for example, a Severity Rating Scale, such as that shown in Table 0.1.
• a severity rating of 1 on the severity scale provided above can indicate full correction of a defect.
• overcorrection can be undesirable.
• treatment and/or re-treatment can correct defects from about 90% to about 100%.
• a maximum of about 100% correction should be administered, without overcorrection, at each treatment.
• the injection site can be massaged to conform to the contour of the surrounding tissues.
• the amount of filler composition administered at each session for any target area can be in the range of from about 0.01 cc to about 1 cc, for example 0.01-0.05, 0.05-0.1, 0.1-0.15, 0.15-0.2, 0.2-03, 0.3-0.4, 0.4-0.5, 0.5-0.6, 0.6-0.7, 0.7-0.8, 0.8-0.9, or 0.9-1 cc.
• each treatment site can be treated with, for example, a maximum dosage of about 1-2, 2-3, 3-4, 4-5 cc per treatment session. If the treated area is swollen directly after the injection, melting ice can be applied on the site for a short period.
• the subject can be evaluated post treatment, which is described in more detail below, hi some embodiments, photographs can be taken prior to each treatment. In some embodiments, the photography can be done in accordance with, for example, the standard Canfield system.
• the amount of injectable filler administered during the re-treatment session is equal to or less than the amount administered in the first treatment session (which can optionally include a touch-up application).
• the amount of filler employed in the re-treatment session is less than 100% of the amount employed for the initial treatment session, for example, 99, 98, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10 percent of the amount employed in the initial treatment session, including any range below any of the preceding values and any amount defined between any two of the preceding values.
• the amount employed in the re-treatment session is approximately 0.01-0.05, 0.05-0.1, 0.1-0.15, 0.15-0.2, 0.2-0.3, 0.3-0.4, or 0.4-0.5 cc for any given target area. In some embodiments, the total amount administered for the re-treatment session is between 1 and 2.5 cc.
• Re-treatment can be performed after the initial treatment. In some embodiments, re-treatment can be performed prior to observation of an unfavourable change in aesthetic improvement. In some embodiments, re-treatment can be performed before an unfavourable change in severity rating according to the Severity Rating Scale occurs. In some embodiments, re-treatment is performed between 1 months and 9 months after the initial treatment. In some embodiments, a re-treatment can be performed about 1 and about 6 months after an initial treatment. In some embodiments, a re-treatment can be scheduled for about 1-2, 2-2.5, 2.5-3, 3-3.5, 3.5-4, 4-4.5, 4.5-5, 5-5.5, 5.5-6, 6-6.5, 6.5-7, 7-7.5, 7.5-8, 8- 8.5, 8.5-9 or more months after an initial treatment.
• Subsequent re-treatments may be performed at any time point subsequent to the previous treatment.
• re- treatment is performed, for example, about one month to about 9 months after a previous treatment session, (either an initial treatment or a subsequent re-treatment).
• this re-treatment session following any previous treatment session is 1-9, 1 -6, 2-9, 2-6, 2-5, 2-4, 3-5, 4-5, or about 4.5 months after the previous treatment.
• the use of a re-treatment session allows for a surprisingly long duration of effectiveness.
• the duration of effectiveness of the dermal filler increases by at least 5%, for example, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150 percent or more (including any range above any of the preceding values and any amount defined between any two of the preceding values).
• the re-treatment session allows for a surprisingly long duration of effectiveness that is at least 6 months, for example, 7, 8, 9, 10, 11, 12, 13, 14 or more months of effectiveness.
• the duration of effectiveness will be 18 months from the initial treatment session.
• using a RESTYLANE® dermal filler in one of the present re-treatment embodiments results in an overall duration of effectiveness of 18 months from the initial treatment session.
• the duration of effectiveness will be at least 6 months from the re-treatment session, for example at least 7, 8, 9, 10, 11, 12, 13, 14 or more months from the re-treatment session.
• the effectiveness is measured in terms of subject satisfaction with the results.
• the effectiveness is measured as at least one point or level of improvement for one of the two scales described herein (WSRS and GAIS).
• administering a re-treatment session less than 6 months from the initial treatment session allows for the above advantage to occur and further allows one to maintain a relatively high level of improvement throughout the duration following the retreatment session.
• an additional administration of an injectable filler when there was no apparent need to supply such an additional amount of an injectable filler.
• performing the re-treatment session well before 9 months, preferably 2 to 6 months after the initial treatment session one not only still obtains the superior long lasting effects identified above, but does so without the dip in WSRS that would have otherwise been present, had one waited for 9 months.
• providing the re-treatment session between 1 and less than 6 months allows one to maintain at least 1 grade of improvement in the subject's WSRS. In some embodiments, at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, or 1.8 points of improvement are maintained throughout an 18 month period. In some embodiments, the above technique allows for the subject to maintain the improvement for a longer part or duration of the time following the re-treatment session.
• the present fractional mean values are most applicable in describing a population of (e.g., two or more) subjects. Thus, in some embodiments, these mean values can be measured across a population of subjects that is being treated.
• One example of the treatment of a population includes performing an initial treatment session on a population of subjects, where the initial treatment session comprises a first injection of a first injectable filler composition into each of the subjects of the population at a target area in each of the subjects, thereby providing an increase in volume and/or firmness to the target areas.
• the method can further include performing a re-treatment session on the population of subjects.
• the re- treatment session comprises a second injection of a second injectable filler composition into the target areas at a time subsequent to the initial treatment session.
• the subject for at least 10% of a 13.5 month period following the re-treatment, will have mean improvement score of at least 1, 1.1, 1.2, 1.3, 1.4, 1 -5, 1.55, or 1.6 to the subject's WSRS, or will have a mean WSRS of no more than 1.9 (e.g., no more than 2.2, 1.9, 1.8, or 1.7).
• the subject for at least 25% of a 13.5 month period following the re-treatment, will have mean improvement score of at least 1, 1.1, 1.2, 1.3, 1.4, 1.5, or 1.6 to the subject's WSRS, or will have a mean WSRS of no more than 2 ⁇ e.g., no more than 1.9, 1.8, or 3.7).
• the subject (or population) will have mean improvement score of at least 1, 1.3 , 1.2, 1.3, 1.4, 1.5, or 1.6 to the subject's (or population's) WSRS, or will have a mean WSRS of no more than 2.05 (e.g., no more than 2, 1.9, 1.8, or 1.7).
• the subject (or population) will have mean improvement score of at least 1.3, 1.4, 1.5, or 1.6 to the subject's (or population's) WSRS or will have a mean WSRS of no more than 2.1 (e.g., no more than 2, 1.9, 1.8, or 1.7).
• the subject (or population) will have mean improvement score of at least 1.3, 1.4, 1.5, or 1.6 to the subject's (or population's) WSRS, or will have a mean WSRS of no more than 2.1 (e.g., no more than 2, 1.9, 1.8, or 1.7).
• the subject (or population) will have mean improvement score of at least 1.1 or 1.2 to the subject ' s (or population's) WSRS, or will have a mean WSRS of no more than 2.3 (e.g., no more than 2.2, 2.1, 2, 1.9, 1.8, or 1.7).
• the subject for 100% of a 13.5 month period following the re- treatment, will have a mean improvement score of at least 1.2 to the subject ' s WSRS, or will have a mean WSRS of no more than 2.3 (e.g., no more than 2.2, 2.1, 2, 1.9, 1.8, or 1.7).
• a mean improvement score of at least 1.2 to the subject ' s WSRS, or will have a mean WSRS of no more than 2.3 (e.g., no more than 2.2, 2.1, 2, 1.9, 1.8, or 1.7).
• the subject ' s (or population's) WSRS will be improved by at least 1.1 for the 13.5 months following the re-treatment session. In some embodiments, the subject's (or population's) WSRS will be at least 1.3, 4.5 months after the re-treatment session. In some embodiments, the subject ' s (or population's) WSRS will be at least 1.3, 7.5 month after the retreatment session. In some embodiments, the subject's (or population's) WSRS will be at least 1.5, 10.5 months after the re-treatment session. In some embodiments, the subject's (or population's) WSRS will be at least 1.7, 13.5 months after the re-treatment session.
• the subject (or population) will have at least a 3.4 mean GAlS throughout the process. In some embodiments, for at least 4.5 of 13.5 months following the re-treatment, the subject (or population) will have at mean GAIS of no less than 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, or 2.9.
• the subject (or population) will have at mean GAIS of no less than 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, or 2.9. In some embodiments, for at least 6 of 13.5 months following the re-treatment, the subject (or population) will have at mean GAlS of no less than 3.5, 3.4, 3.3, 3.2, 3.1 , 3.0, or 2.9. In some embodiments, for at least 9 of 13.5 months following the retreatment, the subject (or population) will have at mean GAIS of no less than 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, or 2.9.
• the subject for 13.5 months following the retreatment, the subject (or population) will have at mean GAIS of no less than 3.4, 3.3, 3.2, 3.1, 3.0, or 2.9. Further optional results and ranges can be found in the examples and tables below. In addition, these values can be generated by the subject and/or the administrator, or a third party, separate from the method. In some embodiments, the magnitude of the result or improvement can be measured at various time points after the re- treatment. In some embodiments, at 4.5 months after the re-treatment, the subject's (or population's) mean WSRS is no more than 2.2 (e.g., less than 2.1 , 2, 1.9, 1.8, or 1.7).
• the subject's (or population's) mean WSRS is no more than 2.1 (e.g., less than 2, 1.9, 1.8, or 1.7). In some embodiments, at 10.5 months after the re-treatment, the subject's (or population's) mean WSRS is no more than 2 (e.g., less than 1.9, 1.8, or 1.7). In some embodiments, at 13.5 months after the re-treatment, the subject's (or population's) mean WSRS is no more than 1.8 (e.g., less than 1.7).
• the subject's (or population's) mean GAIS is at least 3.5 (e.g., at least 3.5, 3.6, or 3.7). In some embodiments, at 7.5 months after the re-treatment, the subject's (or population's) mean GAIS is at least 3.5 (e.g., at least 3.5, 3.6, or 3.7). In some embodiments, at 10.5 months after the re-treatment, the subject's (or population's) mean GAIS is at least 3.7 (e.g., at least 3.7, 3.8, or 3.9). In some embodiments, at 13.5 months after the re-treatment, the subject's (or population's) mean GAlS is at least 3.7 (e.g., at least 3.7, 3.8, or 3.9).
• the re-treatment method described herein provides surprising and unexpected results by employing less dermal filler for at least the same results as would be expected from two separate, traditional, forms of dermal filler applications. In some embodiments, the re-treatment method described herein provides even more surprising and unexpected results by employing less dermal filler for longer lasting and/or a higher level of improvement to the subject.
• an initial treatment injection (of a single side of a subject) receives 1.1+0.61 mL of a dermal filler, and (optionally) have a touch-up application of 0.5+0.22, within two weeks, bringing the total initial treatment session to 1.6 ml (per half of a subject's face), the amount used in the subsequent session is substantially less than 1.6 ml.
• the amount in a re-treatment visit is 0.7+0.33 or 0.7+0.36 (per half of a subject's face), less than half of the 1.6 ml required for the initial treatment.
• the amount administered to a subject is twice that disclosed above (as the above numbers are only representative of one-half of a subject's face). In some embodiments, the amount administered in the initial treatment session is between about 0.8 ml and about 2.4 m] (per half of a subject's face). In some embodiments, the amount given in the first injection of the initial treatment session is between about 0.5 ml and about 1.7 ml , for example, 0.5-1.7, 0.6-1.6, 0.7-1.5, 0.8-1.4, 0.9-1.3, 1-12, or 1 ml (per half of a subject's face).
• the amount provided in an optional touch-up application is between about 0.28 ml and 0.72 ml , for example, 0.28-0.72, 0.3-0.7, 0.4-0.6, or 0.5 ml (per half of a subject ' s face).
• the amount provided for the entire initial treatment session is between about 0.8 ml and 2.4 ml, for example 0.8-2.4, 0.9- 2.3, 1-2.2, 1.1-2.1, 1.2-2, 1.3-1.9, 1.4-1.8, 1.5-1.7, or 1.6 ml (for half a subject's face).
• the amount of filler provided in the re-treatment session is less than 70% of the amount used in the initial treatment session.
• the amount used in the re-treatment session is less than 65, 60, 55, 50, 45, 40, 35, 30, 25, or 20% of the amount used in the initial treatment session, including any range defined between any of the two previous values. In some embodiments, the amount used is between 40% and 50% of the amount used in the initial treatment session, for example 43% or 44%.
• the amount of filler provided in the re-treatment session is less than 90% of the amount used in the first injection of the initial treatment session.
• the amount used in the re-treatment session is less than 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, or 35% of the amount used in the first injection of the initial treatment session, including any range defined between any of the two previous values.
• the amount used is between 60% and 70% of the amount used in the initial treatment session, for example 63% or 64%.
• the amount of filler provided in the re-treatment session is less than 90% of the amount used in a traditional single injection treatment session.
• the amount used in the re-treatment session is less than 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, or 35% of the amount used in a traditional single injection treatment session, including any range defined between any of the two previous values.
• the amount used is between 60% and 70% of the amount used in a traditional single injection treatment session, for example 63% or 64%.
• the subject after the initial treatment, can be evaluated during a follow-up session.
• the follow-up session can be, for example, between one day and two weeks after the initial treatment. In some embodiments, the follow-up session can be two weeks after the initial treatment. In some embodiments, the subject can be evaluated during a series of follow-up sessions ranging from about one day to about 30 months after the initial treatment. In some embodiments, the subject can be evaluated at, for example, about 2 weeks, about 4.5 months, about 9 months, about 12 months, about 15 months, about 18 months, about 24 months, about 27 months and about 30 months after initial treatment.
• the subject can be evaluated for, for example, aesthetic improvement. Assessment can aid in determining a course of future treatment, hi some embodiments, assessment can be done at, for example, the initial treatment visit, two weeks after treatment, and at each subsequent follow-up visit. During visits where treatment is administered, the severity can be rated prior to injection. Aesthetic improvement can be assessed in a variety of ways, including for example, by using a Severity Rating Scale. For example, in some embodiments, a Severity Rating Scale such as the one depicted above can be used to assess the visual appearance of, for example, nasolabial folds.
• each score in the Severity Rating Scale above can be exemplified by, for example, sets of photographs of the area of interest (e.g., nasolabial folds).
• the above chart provides guidelines for an assessment of wrinkle severity at a certain time-point and is not based on a comparison to the pre-treatment appearance. Similar categorical scales can be developed and used for evaluation of a variety different features and areas of interest.
• the methods disclosed provide a favorable change of at least one score in a Severity Rating Scale. In some embodiments, the methods disclosed provide a favorable change of at least two scores in a Severity Rating Scale.
• aesthetic improvement can also be evaluated for global aesthetic improvement, i.e. improvement from pre-treatment appearance, hi some embodiments, the following exemplary categorical scale (in Table 0.2) can be used to measure global aesthetic improvement:
• point values, scores, or grades can be assigned to the above groups.
• the point values, scores, or grades are as follows: 0 - Worse; 1 - No Change; 2 - Improved; 3 - Much Improved; and 4 - Very Much Improved.
• evaluation can be made in view of the overall cosmetic result for each area of interest.
• the ratings can be correlated with the actions that would generally be considered in the normal course of practice. Review of a pre-treatment archival photograph (obtained prior to initial treatment) at each follow-up session can aid in the assessment.
• the methods disclosed provide a favorable change of at least one step in a Global Aesthetic Improvement Scale. In some embodiments, the methods disclosed provide a favorable change of at least two steps in a Global Aesthetic Improvement Scale. In some embodiments, the methods disclosed provide a favorable change of at least three steps in a Global Aesthetic Improvement Scale.
• the assessment is performed at, for example, about two weeks after treatments and at each subsequent visit.
• photography can be used to aid in evaluation of treatment. Photographs can be taken prior to initial treatment. Such photographs can serve as reference for post-treatment assessment of Global Aesthetic Improvement.
• the set of photographs can include at least one direct frontal view centered on the subject's face (i.e., both nasolabial folds are clearly visible).
• archival photographs can be taken at follow-up sessions to, for example, document treatment result.
• the photography can be done in accordance with, for example, the standard Canfield system.
• touch-up of a treatment can be performed. Areas of treatment can be touched-up during, for example, a follow-up session. In various embodiments, the touch-up of a previous treatment is performed. Touch-up can be performed, for example, after an initial treatment or after re-treatment. In some embodiments, touch-up can be distinguished from a treatment or re-treatment because a touch-up occurs within two weeks of a treatment or re-treatment. In some embodiments, a "touch-up" follows an initial treatment session to build upon the adjustments in the previous session in order to obtain a full correction. In some embodiments, a "touch-up" is defined as involving less than 0.5 ml of dermal filler, hi some embodiments, the touch-up is defined as a combination or all of the above.
• scheduling of a subsequent treatment can be arranged based on the timing of a touch-up application.
• a re-treatment can be scheduled between about 4 and about 10 months after a touch-up application.
• a re-treatment can be scheduled for about 1-2, 2-2.5, 2.5-3, 3-3.5, 3.5-4, 4-4.5, 4.5-5, 5-5.5, 5.5-6, 6-6.5, 6.5-7, 7-7.5, 7.5-8, 8-8.5, 8.5-9, 9-9.5, 9.5-10, 10-10.5, 10.5-11, 1 1- 11.5, 1 1.5-12, or more months after a touch-up application.
• the disclosed methods can result in a prolonging of treatment results for more than 18 months after initial treatment.
• earlier re-treatment such as, for example, re-treatment at between about 2 months and about 9 months after an initial treatment session, can provide increased maintenance of treatment results.
• the increased maintenance of treatment results can be without significant decrease in volume during the treatment period. For example, little or no loss of volume can be observed for up to about 18 months after initial treatment, hi some embodiments in which a subject is re-treated within five months of an initial treatment, no significant decrease in volume is experienced for a period of at least about 18 months after initial treatment.
• re-treatment results in maintenance of treatment results at a severity rating without an increase in the severity rating for at least about 18 months after initial treatment. In some embodiments, the severity rating is maintained at mild for at least about 12 months after initial treatment.
• the use of an initial treatment and correctly timed re-treatment can be used to extend the effective lifetime of the initial full correction, hi some embodiments, the improvement score that is obtained from the initial treatment can be maintained for at least a year following the re-treatment session (see, e.g., FlG. 4).
• a relatively early re- treatment session provides the benefit of the earlier re-treatment (maintaining a higher level of improvement score throughout a treatment period), while also providing for the extended duration of effectiveness of the re-treatment (e.g., over a year of maintained improvement).
• the re- treatment session is administered before 9 months (following the initial treatment) and can be, for example 8-7, 7-6, 6-5, 5-4, 4-3, 3-2 months or less following the re-treatment.
• the application of an initial treatment followed by a re-treatment can be used to stimulate an increase in collagen production.
• timely administered re-treatments will provide for an increase in improvement score over several months after the re-treatment session, without requiring the additional injection of the injectable filler.
• the disclosed methods can provide improvement in volume and/or firmness.
• the improvement in volume and/or firmness can occur, for example, gradually over a period of time, ⁇ n some embodiments, the improvement can occur over a period of about one day to about 18 months.
• the improvement can be, for example, a favorable change of at least one score on a severity rating scale. In some embodiments, the improvement can be, for example, a change in severity rating from moderate to mild. In some embodiments, the improvement can be, for example, a change in severity rating from mild to absent. In some embodiments, the improvement can be measured by a favorable change in global aesthetic rating. For example, the improvement can be a favorable change of at least one step on a global aesthetic rating scale. In some embodiments, the improvement can be, for example, a change in rating from improved to much improved. In some embodiments, the improvement can be, for example, a change in rating from much improved to very much improved. In some embodiments, the improvement can be, for example, a change in rating from improved to very much improved. In some embodiments, the improvement can be, for example, a change in rating from improved to very much improved.
• screening evaluations can be conducted prior to treatment.
• the screening evaluations can include, for example, medical history (including any prior dermatological procedures or implants), physical examination, including vital signs, medication history, pregnancy test, and obtaining informed consent, hi some embodiments, women of childbearing potential can have a urine pregnancy test before treatment. Before the treatment, the subject's need for pain relief can be assessed. Local or topical anaesthetics or a dental block can be used, if needed.
• the injectable filler can be, for example, sterile, viscoelastic and, free from products of animal origin.
• the injectable filler can be packaged in, for example, sterile syringes and supplied with a sterilized needle.
• the product can be dispersed in, for example, a physiological saline solution about pH 7.
• the treatment site can be cleaned with a suitable antiseptic solution.
• the injectable filler can be administered using, for example, a thin gauge needle by injecting the material into, for example, the deep dermis and/or the surface layer of subcutis.
• the duration of the implant may be shorter because of a higher filler turnover rate.
• too superficial an injection may give blanching effects and bumps on the treatment site.
• the air may be removed from the syringe up to the point where a droplet is visible on top of the needle.
• the injection technique with regard to the depth of injection and the administered quantity can vary.
• a variety of injection techniques are known in the art and can be used in conjunction with the embodiments described herein.
• the linear threading technique can be used to carefully lift up a wrinkle or fold.
• a series of punctual injections or a combination of the two techniques can be used.
• the eye of the needle preferable faces upwards during injection.
• the contour of the needle can preferably be visible.
• the injectable filler is injected while pulling the needle slowly backwards. Injection can stop just before the needle is pulled out from the skin to prevent material from leaking out from the injection site.
• concomitant medications or other treatments may be utilized when medically necessary.
• Concomitant medications may include, for example, over-the-counter (OTC) medications, and procedures such as, for example, surgery/biopsy or diagnostic evaluations.
• OTC over-the-counter
• the methods and systems disclosed herein allow for improved efficacy of injectable filler compositions. More particularly, some of the embodiments disclosed herein provide methods and systems that prolong the efficacy of injectable fillers for periods of at least about 18 months after initial treatment. Some of the embodiments herein provide methods and systems that provide continuous improvement in volume and/or firmness in a subject. Thus, in some of the embodiments, the methods and systems disclosed herein provide increased aesthetic benefit by prolonging the results of injectable fillers and providing for a continued decrease in wrinkle severity.
• the re-treatment can enhance the effectiveness of the later dermal filler injection session (the re-treatment).
• the initial treatment can aid by maintaining expansile tension and slow the rate of resorbtion following the re-treatment.
• the long lasting effect reported here can be amplified by injection-stimulated collagen production and collagen breakdown inhibition that outlasts the filling of space by the injected gel
• the methods described herein can further include a step of identifying a subject to apply the method to. In some embodiments, this involves identifying a subject that should or would benefit from receiving at least 10 months of improved volume and/or firmness (which can be measured on the WSRS or GAIS in some embodiments). In some embodiments, the step involves identifying a subject that should or would benefit from a continuing increase in volume and/or firmness (which can be measured on the WSRS or GAIS in some embodiments) over a period following a re-treatment and continuing for at least 9, 10, 11, 12, 13, or more months. [0111] In some embodiments, methods and systems disclosed herein provide for ease of training or instruction for improving the efficacy of an injectable filler.
• provided herein are systems and methods that can be, relatively speaking, readily and/or clearly taught. In some embodiments, this involves teaching others how to perform the treatment methods described herein. In some embodiments, the re-treatment method lends itself to ready communication to others and discussion of how and why the technique works. Additionally, in some embodiments, the technique can be readily applied by numerous and different people with different backgrounds. That is, in some embodiments, the teaching of the above treatment methods provides for increased reproducibility of the results described herein with the relevant products. In some of the embodiments, providing users with the knowledge of these methods provides quality control for improving the efficacy of a filler composition.
• a method for teaching a technique that is especially amenable to teaching (and/or the other aspects noted above) is provided, hi some embodiments, the teaching of the method itself also provides the above noted advantages of providing users with a basic technique in common, reproducibility and predictability of results, and allowing a broader range of people to apply the filler.
• the application of the technique itself can have the specific advantages noted herein as well.
• a kit for improving the efficacy of an injectable filler can include a dermal filler, a syringe, a needle, and instructions or guidance for performing parts of or all of some or all of the above techniques.
• the dermal filler is RESTYLANE® or PERLANE® dermal filler.
• the instructions can be provided on a variety of formats, such as electronic (data file, DVD, downloadable, etc) or pamphlets.
• the syringe can be a 2 ml or smaller syringe. In some embodiments, the syringe is prefilled with the derma) filler.
• the kit comprises a first plurality of syringes, wherein each of the first plurality of syringes has a first volume.
• the first volume is between 1 and 5 ml, e.g., 1 , 2, 3, 4, or 5.
• the kit comprises a second plurality of syringes, wherein each of the second plurality of syringes has a second volume and wherein the second volume is approximately one half of the first volume.
• the second volume is between 0.5 and 2.5 ml, e.g., 0.5, 1, 1.5, 2, or 2.5.
• the second volume is approximately 70% of the first volume.
• the kit includes gloves. In some embodiments, the kit includes sterilizing material. In some embodiments the kit includes a cloth or other absorbent material.
• the kit includes software for assisting in capturing images of the subject's face.
• the software compares two facial images of the subject and determines where one should inject and/or re-inject the dermal filler by identifying the areas that appear to lack volume or appear to have lost volume.
• the software compares two facial images of the subject and assesses improvement or worsening of wrinkle severity.
• a training kit can include instructions or guidance for performing parts of or all of some or all of the above techniques.
• the instructions can be provided on a variety of formats, such as electronic (data file, DVD, downloadable, etc) or pamphlets.
• the instructions can generally provide one with any of the steps outlined herein.
• the instructions can include information regarding how much to inject, how to touch-up after an injection, the amount of time to wait before re- treatment, the amount of time it may take for a procedure and for patient recovery after the procedure, the amount of pain that occurs during the procedure, advantages of the re- treatment technique over standard techniques, the results that can be expected, and how the injections should be made in particular situations.
• the training kit includes before and after depictions of subjects that have received the treatment.
• the training kit not only provides training for the user of the technique, but can also provide additional information to help the user sell the technique to potential clients.
• the kit includes information to help the user order additional dermal filler.
• This example illustrates a treatment protocol for maintaining injectable filler efficacy at least as long as one year after re-treatment.
• a subject that desires added volume or firmness is treated with injectable filler. Touch-up with injectable filler can optionally be done within one to two weeks of the initial treatment. At 4 ⁇ /i months after the initial treatment, the subject is retreated with injectable filler.
• One can assess differences in visual severity of the treatment area for example, utilizing the 5-point scale Wrinkle Severity Rating Score (WSRS), at, for example, the initial visit, week two, 4 Vi months (before re-treatment), 9 months, 12 months, 15 months and 18 months. Re-treatment provides prolonged maintenance of treatment results. Aesthetic improvement can also be observed.
• WSRS 5-point scale Wrinkle Severity Rating Score
• This example illustrates generally a study involving a treatment protocol to prolong RESTYLANE® dermal filler efficacy at least as long as one year after re-treatment.
• the objective of the study outlined in this example was to evaluate the efficacy of RESTYLANE® dermal filler for the correction of nasolabial folds (NLF) and the effect of different re-treatment schedules to affect the persistence of a cosmetic improvement.
• Study findings demonstrated a duration of effect with RESTYLANE® dermal filler resulting from 4 1/2 and 9 month re-treatment sessions (85 percent and 88 percent, respectively). Furthermore, with a re-treatment at 9 months, 97 percent of subjects maintained response at 18 months.
• Blinding was accomplished by utilizing one medically qualified individual to administer the treatments and an evaluating investigator ⁇ who was blinded to the randomization) to conduct the NLF evaluations.
• the study measured differences in visual severity of the nasolabial folds, utilizing the 5-point scale Wrinkle Severity Rating Score (WSRS), as assessed by the evaluating investigator at initial visit, week two, 4 Vi months (before re-treatment), 9 months (before re-treatment), 12 months, 15 months and 18 months.
• WSRS 5-point scale Wrinkle Severity Rating Score
• a responder was defined as anyone who had achieved at least a one grade improvement in WSRS at any time point.
• This study enrolled a total of 75 subjects with a mean population age of 53.8 years (range 26-73). Subjects were excluded from the study if they had undergone procedures based on active dermal response (e.g., laser and chemical peeling procedure) within 6 months prior to study start or if they had any facial tissue augmenting therapy or aesthetic facial surgery within 9 months prior to study start. Study participants were predominantly Caucasian female, and only 8 percent of those enrolled had undergone prior augmentation therapy. Mean baseline WSRS was 3.2 (0-4 scale) in the NLF, and there was no statistical difference in WSRS between the side re-treated at 4 Vi months and the side retreated at 9 months.
• active dermal response e.g., laser and chemical peeling procedure
• This example illustrates one possible design of a study for comparing re- treatment at different time points. As will be appreciated by one of skill in the art, the study can be repeated to examine various durations, injectable fillers, and other variables.
• the objective of this example is to evaluate the efficacy of injectable fillers for the correction of nasolabial folds and the effect of the re-treatment schedule on the overall persistence of the implant.
• the primary objective is to evaluate the duration of efficacy of injectable fillers, after multiple treatments and at different time points, in regards to differences in visual severity of the nasolabial folds, as assessed by, for example, the Evaluating Investigator at different time points.
• the primary endpoint can be, for example, the scores in the Severity Rating Scale, obtained at visits.
• a secondary objective of the study in this example can include, for example: severity of the wrinkles at other time-points during the study and as assessed by the subject, and Global Aesthetic Improvement as judged by the Evaluating Investigator and the subject.
• Nasolabial folds are fairly large, bilateral fissures that can be augmented and assessed with relative ease. Augmentation to fill the groove is the clear goal of treatment.
• Each subject can serve as their own control by randomly assigning the test and control treatment to contralateral sides of the face (although these lesions can not be the exactly same size, they can be close and the randomization procedure can reasonably be expected to balance size across the study population). This type of trial can also balance the randomization for skin type or other factors that might affect the outcome.
• trials of reasonable duration (6-12 months) can reliably detect the loss of augmentation (or degree of correction) associated with biodegradable implants. Gormley et al, J Dermatol Surg Oncol 1990:16(12):! 147-1151, incorporated herein in its entirety.
• biodegradable implants involves the assessment of "short-term” and ''long-term 1' responses.
• Short-term responses can include the initial degree of correction, adverse events associated with the injection of the implant (e.g., pain, swelling, erythema, bruising, or itching), and the time course for resolution of any injection-related adverse events. Based on clinical experience, the majority of short-term injection-related adverse events would be expected to develop quickly and resolve within a few days of the implantation procedure.
• Long-term responses can include any late-developing adverse events and persistence of the implant. With respect to the overall efficacy of a biodegradable implant it would appear that the most important issue is the duration of effect.
• the study can employ a randomized, evaluator-blind design and follow the protocol outlined in FIG. 1.
• One of the nasolabial folds can be randomly assigned to be corrected with injectable filler and then re-treated at 4 1 A months. The opposite side can be treated with injectable filler and not re-treated until 9 months. Both nasolabial folds can then be re-treated at 18 months.
• Each subject can serve as their own control, allowing comparison of the outcome between the contralateral sides.
• Blinding can be accomplished by utilizing one qualified individual to administer the treatments and a second medically qualified individual (who is blinded to the randomization) to conduct the direct evaluations. The subjects can be aware that they are receiving both treatment schedules.
• Visit 3 (4 V 2 months) Subject WSRS n(%)
• GAI Global Aesthetic Improvement
• the objective of the initial treatment was to achieve an "optimal cosmetic result" on each side of the face.
• An “optimal result” is defined as the best possible cosmetic result that was obtained for an individual study participant with the two injectable implants (as determined by the Evaluating Investigator). After the initial implant session, the subject is evaluated after post treatment. Photography with standard Canfield system is done at all visits prior to treatments.
• Visit 1 Baseline/Screening
• Visit 2 Week 2
• Visit 3 month 4 ⁇ ⁇
• Visit 4 month 9
• Visit 5 month 12
• Visit 6 month 15
• Visit 7 month 18
• Visit 8 month 24
• Visit 9 month 27
• Visit 10 month 30
• touch-ups were given at 2 weeks
• a Follow-Up visit Visit T
• another 2 Week Follow-Up visit Visit 2
• Visit 3 is calculated from the last touch-up visit.
• one side of the nasolabial fold was re-treated to optimal cosmetic correction.
• the contralateral side was re-treated to optimal cosmetic correction.
• the total duration of a subject's participation in the trial was approximately 29-30 months from the time of initial screening until the final follow-up.
• Individuals eligible for inclusion in the study include the following: males or non-pregnant, non-breast feeding females aged 18 years or older, subjects seeking augmentation therapy for correction of bilateral nasolabial folds, subjects with a score of 3 or 4 on the Severity Rating Scale, subjects with the ability to understand and comply with the requirements of the trial, subjects willing to abstain from exclusionary procedures (e.g.. further augmentation therapy, laser or chemical resurfacing; and BOTOX® injections below eye level; facelift) for the duration of the study.
• exclusionary procedures e.g. further augmentation therapy, laser or chemical resurfacing; and BOTOX® injections below eye level; facelift
• tissue augmenting substances BOTOX® injections below the level of the eye-brows, and facelift; concomitant anticoagulant therapy, antiplatelet therapy, or a history of bleeding disorders; subjects who have previously experienced unanticipated adverse reactions when treated with hyaluronic acid based products; any condition which in the opinion of the investigator makes the subject unsuitable for inclusion (e.g., subjects not likely to avoid other treatments, subjects not likely to stay in the study for six months, or subjects anticipated to be unreliable; subjects with cancerous or pre-cancerous lesions in the area to be treated; and use of any investigational drugs or devices within 30 days prior to randomization.
• the injectable filler used in this example was RESTYLANE® dermal filler.
• RESTYLANE® dermal filler is manufactured, packed and labelled by Q-Med AB, Uppsala, Sweden.
• RESTYLANE® dermal filler is a clear, colourless and transparent gel which includes 20 mg/ml of stabilized hyaluronic acid. The gel is sterile, viscoelastic and, free from products of animal origin. Pre-testing for hypersensitivity is not required. It is packaged in sterile 1.0 mL syringes and supplied with a sterilized 27G x Vi inch needle. The product is dispersed in a physiological saline solution pH 7.
• RESTYLANE® dermal filler was administered using a thin gauge needle by injecting the material into the deep dermis and/or the surface layer of subcutis. If RESTYLANE® dermal filler was injected too deep or intramuscularly, the duration of the implant was shorter because of a higher hyaluronic acid turnover rate. Too superficial an injection can give blanching effects and bumps on the treatment site.
• the injection technique with regard to the depth of injection and the administered quantity can vary.
• the linear threading technique was used to carefully lift up the wrinkle or fold, but some operators preferred a series of punctual injections or a combination of the two.
• the eye of the needle face upwards.
• the contour of the needle should be visible but not the colour of it.
• the injection site were massaged to conform to the contour of the surrounding tissues. For each treatment site a maximum dosage of about 1.5 ml per treatment session was recommended.
• Treatment Schedule A involved the right side being re-treated with Restylane at AVz months (left side untreated at 4/4 months) and the left side being re-treated with Restylane at 9 months (right side untreated at 9 months).
• Treatment Schedule B involved the left side being re-treated with Restylane at 4Vi months ( ⁇ ght side untreated at 4 ] /i months) and the ⁇ ght side being re-treated with Restylane at 9 months (left side untreated at 9 months).
• the P-value was from a paired Student's t-test
• the trial in this example included two administrations of the implants by the Treating Investigator. As a result, compliance did not require further assessment.
• the subject ' s need for pain relief can optionally be assessed.
• Local or topical anaesthetics or a dental block can be used, if needed. Any such use should be recorded in the CRF.
• concomitant medications or other treatments can be utilized when medically necessary. Any concomitant medication, including over-the- counter (OTC) medications administered, or any concomitant procedures such as surgery/biopsy or diagnostic evaluations performed during the study were recorded on the case report form (CRF).
• OTC over-the- counter
• CRF case report form
• the generic name of the concomitant medication (or a description of the procedure) and the reason for its use can also be provided on the CRF Administration of anticoagulants (e g., warfarin) or inhibitors of platelet aggregation (e.g., aspirin or other nonsteroidal anti-inflammatory drugs) are excluded beginning three weeks prior to the treatment visit and extending until the injection sites are completely healed (unless medically necessary, this exclusion should extend for at least four weeks after treatment).
• anticoagulants e g., warfarin
• inhibitors of platelet aggregation e.g., aspirin or other nonsteroidal anti-inflammatory drugs
• At least one independent Evaluating Investigator is designated at each study site. This investigator is blinded to treatment assignment and can perform all of the efficacy evaluations. The Evaluating Investigator can make the efficacy assessments in the study, and may take part in the care of the subject after the injection.
• a Severity Rating Scale was used to assess the visual appearance of the nasolabial folds. It is an assessment of wrinkle severity at a certain time-point and is not based on a comparison to the pre-treatment appearance. The assessments were made by the blinded, independent Evaluating Investigator and used as the primary efficacy measurement in the study. The Evaluating Investigator rated each nasolabial fold separately (right and left) for severity using the following categorical scale (Table 4.7).
• Each score in the Seventy Rating Scale was exemplified by a set of three photographs of nasolabial folds. A favorable change of at least one score in the Severity Rating Scale is defined as a clinical significant improvement. [0159J The assessment was performed at the treatment visit ⁇ Visit 1), two weeks after treatment (Visit 2) and at each subsequent Follow-Up Visit. During visits where treatment is administered, the severity is rated prior to injection.
• the Severity Rating Scale was also used by the Treating Investigator at study entry to assess the inclusion criteria.
• the subjects can assess the visual appearance of each nasolabial fold separately (right and left) using the following categorical severity scale (Table 4.8).
• the assessment can represent wrinkle severity at a certain time-point and not be based on a comparison to the pre-treatment defect level.
• Each score in the Severity Rating Scale is exemplified by a set of three photographs of nasolabial folds.
• a favourable change of at least one score in the Severity Rating Scale is defined as a clinically significant improvement.
• the Evaluating Investigator made this assessment in view of the overall cosmetic result for each contra lateral fold. The ratings were correlated with the actions that would generally be considered in the normal course of practice. The Evaluating Investigator could optionally review the pre-treatment archival photograph (obtained prior to injection of the implants at Visit 1) at each visit to aid in the assessment.
• the subjects also rated the global aesthetic improvement of each nasolabial fold, relative to pre-treatment appearance, using the above categorical scale.
• the subject was asked to evaluate the overall improvement in the appearance of each nasolabial fold.
• the subject was instructed to select the one rating which best describes the degree to which the appearance of nasolabial fold has been improved by the implant relative to pre-treatment.
• the subject could have reviewed the pre-treatment archival photograph (obtained prior to injection of the implants at Visit 1) at each visit to aid in the assessment.
• Photographs taken at the "Screening and Treatment Visit” (Visit 1) served as reference for the Evaluator's and Subject's post-treatment assessment of Global Aesthetic Improvement.
• the photographs were obtained in an as standardized manner as possible, in accordance with the practice of the study facility.
• the set of photographs could have included at least one direct frontal view centered on the study participant's face (both nasolabial folds should be clearly visible).
• Each photograph should have been labeled with the study participant's randomization number, initials and date of photograph.
• Archival photographs are taken at scheduled visits during the study (to document treatment result).
• the Severity Rating Scale and the Global Aesthetic Improvement Scale are ordered categorical measures.
• the primary efficacy evaluation was based on a responder criterion.
• a subject was defined as a responder for the treatment (wrinkle) if there was an improvement of at least one step in the Severity Rating Scale (assessed by the investigator) from the value prior to treatment (visit 1) to the value at 4 1/2, 9 and 12 month respectively (visit 3, 4, and 5).
• the safety population included all subjects who received an implant with either the test or control device.
• the Intent-to-treat (ITT) population included all subjects, who were randomized and treated.
• the Per-protocol (PP) population included all subjects in the intent-to-treat population who had all efficacy evaluations at all time points and who had no major protocol deviations.
• NASHA s effective correction of nasolabial folds persisted for at least 18 months post-initial treatment and at least 9 to 13.5 months post-retreatment, regardless of re- treatment schedule. Almost all patients (97%) had at least 1 grade improvement at 18 months (13,5 or 9 months post-re-treatment) and many had 2 grades improvement.
• Early re- treatment can be superior as patients do not experience an increase in wrinkle severity before receiving a second treatment and the response is maintained for at least 1 year. The earlier re-treatment appears to maintain tissue expansile tension and slow gel resorption so that results are the same regardless of re-treatment schedule.
• the long lasting effect reported here can be amplified by injection-stimulated collagen production and collagen breakdown inhibition that outlasts the filling of space by the injected gel.
• FIG. 3 summarizes the results for Responder analysis of the wrinkle severity rating score between the AVi and 9 month re-treatment schedule over time.
• FlG. 4 summarizes the mean improvement score results for the wrinkle severity rating score between the A 1 A and 9 month re-treatment schedule over time.
• FIG. 5 summarizes the results for the wrinkle severity rating score between the AVi and 9 month re-treatment schedule over time.
• FIG. 6 summarizes the mean improvement score results for the completers for the wrinkle severity rating score between the AVz and 9 month re-treatment schedule over time.
• FIG. 7 summarizes the mean improvement score results for the wrinkle severity rating score between the AVi and 9 month re-treatment schedule over time.
• the "0" time period is the time period starting after the re- treatment step.
• some of the above embodiments can be employed to provide Evaluator and participant mean Wrinkle Severity Rating Scale score improvement of 0.7 grades at 2 weeks and of 1.6 grades at 18 months and of 0.7 to 1.0 grades across 7 visits, respectively.
• Evaluator and participant Global Aesthetic Improvement Scale ratings can provide improvement from 2.4 points at 2 weeks to 3.7 points at 18 months and from 2.4 to 3.2 points across the 7 visits, respectively.
• any improvements or results demonstrated in FIGs. 3-7 can be achieved through the use of various embodiments disclosed herein.
• the proportion of subjects with at least one grade improvement in WSRS was similar between the two sides (97% of the A 1 A month re-treated side and 95% of the 9-month re-treated side).
• the mean improvement from baseline in WSRS score was more than 1 grade for each side at all time points.
• the mean change from baseline in WSRS for both re-treated sides was similar to the change from baseline noted at 2 weeks after re-treatment (1.6 to 1.7 at 18 months; 1.7 at 2 weeks after re-treatment).
• the mean improvement from baseline in WSRS score ranged from about 0.9 to 1.3 for the 4 1 A month re-treated side and about 0.8 to 1.3 for the 9 month re-treated side.
• the mean change from baseline in WSRS for both re-treated sides was similar to the change from baseline noted at 2 weeks after re- treatment ⁇ 1.1 at 18 months; 1.2 to 1.3 at 2 weeks after re-treatment).
• the mean change from baseline at all visits was statistically significant (pO.OOl) for all follow-up Blinded Evaluator and subject assessments.
• GAIS Global Aesthetic Improvement Scale
• Tables 5.5 and 5.6 below provide the proportion of subjects with at least on grade improvement in Global Aesthetic Improvement Scale (GAIS) from baseline by visit.
• GAIS Global Aesthetic Improvement Scale
• Table 5.5 shows the treating investigator's assessment
• Table 5.6 shows the subject's assessment.
• Improvement from baseline was consistently affirmed by both Treating Investigator and subject. Most subjects assessed by the Treating Investigator (98% to 100%) and subjects (94% to 100%) had at least a one grade improvement from baseline on the GAlS at all follow-up visits.
• the mean GAIS scores as assessed by the Treating Investigators and subjects ranged from 3.0 to 3.7 (Much Improved) for both treated sides at all visits after re- treatment.
• Tables 5.7 and 5.8 below provide the mean GAIS by visit.
• Table 5.7 shows the treating investigator's assessment, and
• Table 5.8 shows the subject's assessment.
• a panel of three Independent Photographic Reviewers evaluated WSRS scores of photographs taken at all study visits. Each reviewer reviewed the photographs independently and assigned a WSRS to each photograph. This analysis resulted in about 76% to 87% of subjects achieving at least a one grade improvement from baseline in WSRS scores and a mean change from baseline in WSRS score that was greater than one grade improvement at 18 months. Table 5.9 below provides the results from the independent photographic review.
• the proportion of subjects achieving at least a one grade improvement from baseline after re-treatment as assessed by IPR was from 76% to 87% for the 4 ⁇ ⁇ month re-treated side and 82% to 85% for the 9 month side.
• the mean change from baseline in WSRS for both re-treated sides was > 1 grade improvement from baseline, similar to the change from baseline noted at 2 weeks after re-treatment.
• Table 5.10 below depicts the proportion of subjects with at least one grade improvement in WSRS from baseline by visit (independent reviewers' assessment).
• Table 6.11 depicts the mean WSRS and mean improvement in WSRS from baseline by visit (independent reviewers' assessment).
• the mean change from baseline in WSRS score was more than 1 grade for each side at all time points.
• the mean improvement from baseline in WSRS score was more than 1 grade and was similar to the change from baseline observed at 2 weeks after re-treatment for each side.
• the mean change from baseline at all visits was statistically significant (p ⁇ 0.001) for all follow-up Blinded Evaluator and subject assessments.
• the mean volume injected ⁇ in mL) at each treatment is summarized in Table 5.12.
• the mean volume of Restylane injected into each nasolabial fold during the initial treatment was similar between sides.
• the AVi month re-treatment side and the 9-month re-treatment side received virtually identical mean volume of RESTYLANETM dermal filler, 1.1 mL at baseline and 0.5 mL at the touch-up visit.
• the mean volume injected at re- treatment (0.7 mL for re-treatment at either AVi or 9 months) was less than at the initial treatment and was only slightly more than the amount required at the touch-up visit (0.5 mL for each re-treatment side). This shows that, even for subjects with a more extreme WSRS, the subjects required less product to achieve optimal correction at re- treatment.
• the amount of the injectable filler composition used in the re-treatment session was only around 0.7 cc, compared to the 1.1 and 0.5 injections in the initial treatment session (per half of a subject's face).

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