Patients often seek treatment to enhance the appearance of their hands in addition to their face, as hands are the second leading indicator of age after face.1 This is particularly true for individuals who have undergone facial procedures, as these patients are often bothered by the discrepancy between the youthfulness of their face and the aged appearance of their hands. Common concerns include irregular surface pigmentation that can be due to sun exposure, and more prominent visibility of veins and tendons due to loss of subcutaneous fat.
Radiesse (Merz North America, Inc., Raleigh, NC), is an opaque, white-colored injectable dermal filler composed of calcium hydroxylapatite (CaHA) microspheres suspended in a gel carrier. CaHA injected into the dorsum of the hand has been shown to provide immediate volume correction,2,32,3 and was approved in Canada in 2010 for the treatment of volume loss in the dorsum of the hands. In 2015, CaHA became the first and only filler to be approved in the United States to correct volume loss in the dorsum of the hands.4 Previously, products such as autologous fat5 and hyaluronic acid6 have been used.7 CaHA is also approved for the correction of moderate to severe facial wrinkles and folds, including nasolabial folds, and is indicated for correction of the signs of facial fat loss (lipoatrophy) in people with human immunodeficiency virus.8
Treatment success after a cosmetic procedure can be measured subjectively with patient satisfaction questionnaires, or more objectively, with the use of validated clinical assessment scales.9–139–139–139–139–13 The 5-point photonumeric Merz Hand Grading Scale (MHGS) was designed as an assessment tool for physicians to quickly and reliably evaluate the appearance of the dorsum of the hand. The MHGS has been rigorously validated for this purpose in photographic and live assessments.14–1814–1814–1814–1814–18
The primary objective of this study was to assess the sensitivity of the validated MHGS to detect clinically meaningful changes in the appearance of the dorsum of the hand after treatment with CaHA. In addition, this study investigated whether changes on the MHGS were clinically meaningful and aesthetically pleasing with the use of the GAIS and subject satisfaction assessments, respectively.
This prospective, randomized, controlled, 4-week study at 2 Canadian investigational sites enrolled healthy subjects who were candidates for hand treatment. The clinical study was conducted in accordance with applicable regulations inclusive of Institutional Review Board (IRB) approval by Veritas IRB Ethics Committee (Montreal, Canada). Written informed consent was obtained from each eligible subject before enrollment into the study. Subjects between 18 and 65 years of age were assessed for inclusion if both their right and left hands had a rating of 2 or 3 on the MHGS as determined by a masked evaluator.14
Once enrolled, subjects were randomized 2:1 to either the Treatment group or the Control group corresponding to a predetermined randomization sequence. After collection of the required data for the analysis between these 2 groups, the Control group was crossed over and received treatment. Treatment group subjects were followed for 1 month from study enrollment. Assessments were done at Week 1, Week 2, and Week 4.
Subjects assigned to the Treatment group were treated at enrollment with CaHA dermal filler; Control group subjects received delayed treatment at Week 4 (after completion of all effectiveness assessments).
Before treatment, 0.26 mL of 2% lidocaine HCl was mixed in-office with each 1.5 mL syringe of CaHA, in accordance with the mixing procedure described in the Canadian Radiesse Instructions for Use.8 The final product had a medium viscosity for dermal fillers, as previously reported.19 Preop instructions included washing of the hands and cleaning the dorsal treatment areas with antiseptic. There was no preop anesthesia administered, other than mixing of CaHA with lidocaine. Subjects received injections in the dorsum of both hands between the first and fifth metacarpals using a 27-gauge needle. Skin tenting was performed with the noninjecting hand to separate the skin from underlying vasculature and tendons. The volume of CaHA injected was at the discretion of the treating physician, who determined the optimal cosmetic result for each hand. A multi-bolus technique was used and injections were given in small boluses of 0.2–0.5 mL per bolus. Each subject received 1 treatment of no more than 3 mL per hand. Subjects were instructed to sit on their hands after the injection, and ice was applied at the discretion of the treating investigator. The dorsum of the hand was gently massaged until the CaHA was evenly distributed across the dorsum. After the procedure, subjects were instructed in appropriate care, which included (1) application of ice or cool compresses for approximately 24 hours, (2) avoiding sun or tanning, or (3) massaging the area if palpable nodules become present.
Demographic information for each subject was collected at Baseline. Individual MHGS assessments were made for each hand at Baseline and at Week 2 and 4 visits. Photographs were also taken at Baseline, Week 2, and Week 4 using standardized photography.
The MHGS ratings were made from live assessment of subject hands performed by evaluators masked to the randomization assignments of the subjects. There was 1 masked evaluator qualified to perform this task at each site. Blinding was maintained by not allowing raters to observe subjects entering and leaving the room, not allowing conversation between subjects and raters, and properly positioning the hand to be evaluated under a custom curtained frame, so that raters could not see the subject's face and upper torso.
Before study initiation, masked evaluators were trained and qualified by the study sponsor to perform live assessments using the MHGS. Weighted Kappa analysis was performed to ensure that qualified evaluators exhibited substantial intrarater and interrater reliability.
The GAIS was used to determine if changes on the MHGS were clinically and aesthetically meaningful. The GAIS assessments at Week 2 and Week 4 were photo-to-photo review ratings performed by the same qualified evaluators masked to subject randomization assignments. In addition, treating physicians and subjects in the Treatment group assessed each hand live using the GAIS at Week 4 relative to pretreatment Baseline photos. The GAIS ratings are described in Table 1.
To determine whether changes were aesthetically pleasing, treating physicians and subjects in the Treatment group also completed physician and subject satisfaction questionnaires, respectively. For all subject satisfaction responses, each Treatment group subject compared their hands during the Week 4 study visit with pretreatment Baseline photos.
Adverse events were assessed immediately after treatment and at all subsequent visits by the treating physician. Subjects in the Treatment group were given a 30-day Subject Diary and instructed to provide daily entries to record potential and prespecified adverse events, including bruising, itching, pain, redness, and swelling of their hands. Subject diaries were reviewed at each visit for adverse events. If an adverse event in the subject diary was also observed by the investigator, that specific adverse event was counted only once during the safety analysis.
Safety was also evaluated using a series of real time hand function tests which assessed range of motion, sensation, dexterity, and grip and pinch strength. All subjects (both Treatment and Control groups) were also evaluated using various real time hand function testing procedures. Hand function tests were performed after hand photography at Baseline, Week 2, and Week 4. Results from these hand function tests will be reported in a separate publication.
To determine sample size, it was assumed that the Treatment group hands would have a success rate of 60% and the Control hands would have a success rate of 20%. Using 80% power and a 1-sided significance level of 0.025, it was determined that 36 hands were needed in the Treatment group and 18 hands were needed in the Control group.
Analysis of each individual hand was performed to determine if the MHGS could detect changes in the dorsum of the hand 4 weeks after treatment. The threshold of improvement with the MHGS was a 1-point improvement. The primary outcome was the number of subjects in the Treatment group achieving a ≥1-point improvement in both hands on the MHGS from Baseline at Week 4, and if the improvement was statistically significant compared with the untreated Control group. The level of significance was ≤0.05 using a 2-sided paired t-test. Secondary outcomes were analyzed in an exploratory and descriptive way, and included effectiveness measured using the GAIS, physician and subject satisfaction questionnaires, and hand function tests.
Of the 41 subjects screened between January 2012 and February 2012, 20 were randomized to the Treatment group and 10 were randomized to the Control group. Of the 11 screen failures, 5 did not receive a hand rating of 2 or 3 on the MHGS, 4 had current or recurrent inflammation or infection, 1 was unable to meet all study requirements, and 1 had received systemic steroids within the past 2 months. Overall, 28 subjects were treated; 2 subjects in the Control group declined treatment at Week 4. Treatment results of the Control group were not required for analysis of the primary effectiveness endpoint. Mean (range) age of subjects was 52 years (37–65). Subjects were predominantly female (28/30; 93.3%) and white (27/30; 90%), and of diverse Fitzpatrick Skin Types (Table 2).
Mean total injection volume for both hands among all treated subjects was 4.5 ± 2.0 mL (range 1.7–7.2). The mean bolus volume was 0.26 mL and the mean number of total boluses per subject was 17.5.
Evaluator Merz Hand Grading Scale Training and Qualification
The intrarater and interrater agreement analysis for scale qualification demonstrated that each of the masked evaluators rated hands consistently when compared with their own evaluation and when compared with each other. The masked evaluators were very consistent within themselves, with intrarater weighted Kappa values for each of the 2 evaluators to be 0.97 and 0.85, respectively. High agreement between the 2 evaluators at the 2 sites was demonstrated by the interrater weighted Kappa value (0.88). The almost perfect strength of agreement in results of the qualification weighted Kappa analysis demonstrated that the masked evaluators were using the MHGS in a consistent and reproducible manner before the initiation of the study.
Significant Improvement in MHGS Ratings After CaHA Treatment
A statistically significant improvement in the MHGS ratings relative to Baseline was demonstrated in the Treatment group compared with the Control group. At Week 4, each subject (20/20) in the Treatment group achieved a ≥1-point improvement on the MHGS compared with 0/10 (0%) of the Control group (P < .0001) (Figure 1). The mean change (SD) in MHGS rating was −1.8 (0.5) for hands in the Treatment group versus 0.0 (0.0) for hands in the Control group at Week 4. Furthermore, there was symmetry of improved hand appearance (equal MHGS ratings) in 100% of the treated subjects.
Improvement in MHGS Rating After CaHA Treatment Corresponds With Improvement in GAIS Rating and Subject Satisfaction
GAIS ratings were reported from 3 sources: masked evaluator assessment, treating physician assessment, and subject assessment. Masked evaluators performed a photo review for GAIS ratings, and rated 100% (40/40) of hands as at least “improved” (Figure 2). Subjects and treating physicians compared the appearance of the hands live at 4 weeks after treatment with Baseline photographs. Similar to the masked evaluator, the treating physicians rated 100% (40/40) of hands as at least “improved” on the GAIS (Figure 2). The vast majority of subjects, 92.5% (37/40) rated their own hands as at least “improved” (Figure 2), indicating that subject-reported treatment outcomes corresponded to the ≥1-point MHGS improvement as rated by the masked evaluator in all hands (Figure 1).
Based on the satisfaction questionnaire results, most subjects in the Treatment group were “Extremely Satisfied” (13/20; 65%) or “Satisfied” (3/20; 15%). Treating physicians were also “Extremely Satisfied” (15/20; 75%) or “Satisfied” (4/20; 20%) with treatment outcomes (Figure 3). In addition, 80% of subjects rated their hands as “Look Much Younger” (survey on youthfulness of appearance) compared with those before treatment, and 70% indicated that they would be “Somewhat Likely” to “Extremely Likely” to return for future hand treatment (survey on likelihood to return for future hand treatments).
Before and after pictures show typical improvement in hand appearance 4 weeks after treatment (Figure 4). At Baseline, each hand was rated 3 on the MHGS by a masked evaluator. Four weeks after treatment with a total volume of 4.0 mL of CaHA mixed with lidocaine for both hands, both hands were rated 1 on the MHGS by the same masked evaluator. Both the subject and the treating physician rated the Week 4 images as “Very Much Improved” on the GAIS compared with Baseline photos. The masked evaluator rated the Week 4 images as right hand “Much Improved” and left hand “Very Much Improved” on the GAIS compared with Baseline photos. The subject rated her hands as “Look Much Younger” compared with Baseline photographs.
Subjects reported 61% (n = 146) of all adverse events and the treating physicians reported the remaining 39% (n = 95) (Table 3). Most subject-reported adverse events were of mild or moderate severity and all resolved within 7 days.
The most common adverse event reported was swelling. All 20 Treatment group subjects experienced swelling for a total of 35 swelling events with mean duration of approximately 7 days. Swelling was not related to volume injected (range 1.7–7.2 cc), and 17% of subject-reported swelling events had onset >14 days post treatment. Five of 20 subjects reported “severe” swelling, with 11 of 20 subjects experiencing a recurrence of swelling >3 days after the initial resolution. Only 1 of 20 subjects received intervention for swelling, which consisted of a topical steroidal treatment prescribed on day 16 with resolution by day 24. No nodules were reported during the study.
Hand function test results indicated no negative effect on hand function as a result of CaHA hand treatment. Results from the hand function tests will be reported in a separate publication.
CaHA injections were well tolerated for hand treatment with a mean total treatment volume of 4.5 mL. The majority of adverse events reported in this study were expected, generally short in duration, and typical of dermal filler injections.
As the dermal filler market continues to grow, an increasing number of products and procedures are available to help patients maintain a youthful facial appearance. However, many patients who use these products and treatments are bothered by the fact that their hands show signs of volume loss, and increased prominence of veins and tendons. The disparity between their perceived age based on their face and that of their hands is one of the reasons why soft tissue filler treatments of the hand have become increasingly popular with patients. Over time, the hands may experience loss of dermal elasticity and atrophy of subcutaneous tissue, giving them a sunken, often bony appearance, and resulting in more prominent appearance of veins and tendons. Until recently there has been no approved dermal filler option in the United States. CaHA is the first and only dermal filler to be approved in the United States to correct volume loss in the dorsum of the hands.
Previous work validated the MHGS as a tool to characterize the appearance of hands based on clinical and aesthetic signs and symptoms (loss of fatty tissue, visibility of veins and tendons) with high intrarater and interrater reliability.14–1614–1614–16
These previous studies validated the MHGS as a tool to quickly and easily measure the effectiveness of CaHA-based dermal filler in changing the appearance of the hands. Results from this study add to this by demonstrating that a 1-point improvement in the MHGS rating after CaHA treatment corresponds to a clinically meaningful and aesthetically pleasing improvement in hand appearance. In all cases where the masked evaluator assessed a clinically meaningful ≥1-point MHGS improvement, the GAIS rating was also at least “improved” in the vast majority of hands as reported by subjects and by treating physicians. These results highlight the usefulness of the MHGS in daily practice, allowing physicians to more easily manage patients' expectations and to determine satisfaction with treatment results.
The MHGS can also be used as a tool to facilitate communication between physicians and patients to raise awareness of options that exist to enhance the appearance of the hand. The MHGS can be used to initiate a discussion about the possibility of hand treatment, which some patients may not even know exists, and to explore the range of treatment effects that can be expected with CaHA treatment.
Restoring volume in subjects with moderate to severe loss of fat tissue in the dorsum of hands with CaHA is well tolerated and produces a statistically significant improvement in hand appearance. This randomized, controlled, single-blind study demonstrates that live assessment based on the MHGS can objectively detect improvements in hand appearance 4 weeks after treatment with CaHA. Importantly, the study demonstrates that a ≥1-point rating change on the MHGS scale is clinically meaningful and aesthetically pleasing, providing a clinically valuable tool to physicians and patients. In addition to being required to obtain FDA approval, the MHGS can be used to improve communication between physicians and patients, assisting patients in making informed choices and assessing changes after treatment. Additionally, the MHGS is a useful tool that may be used to train new practitioners and to assess the efficacy of soft tissue filler hand treatments in clinical trials.
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