Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials.

BACKGROUND: ATX-101 (deoxycholic acid injection) is the only injectable drug approved for submental fat (SMF) reduction. In the phase 3 REFINE trials, adults with moderate or severe SMF who were dissatisfied with the appearance of their face/chin were eligible to receive up to 6 treatment sessions with ATX-101 (2 mg/cm2) or placebo. Primary and secondary endpoints, evaluated at 12 weeks after last treatment, significantly favored ATX-101 supporting its efficacy for reducing SMF and the psychological impact of SMF, and increasing satisfaction with the appearance of the face/chin. OBJECTIVES: To evaluate the efficacy and safety of ATX-101 by treatment session. METHODS: This post hoc analysis used pooled data from the REFINE trials to evaluate efficacy endpoints and adverse events following each treatment session to further characterize the ATX-101 treatment response and safety profile. RESULTS: In both treatment groups, mean injection volume declined over subsequent treatment sessions, though more markedly in the ATX-101 group. The majority of ATX-101-treated patients achieved a ≥1-grade improvement in SMF within 2 to 4 treatment sessions based on either clinician or patient assessment. Furthermore, 19.1% of ATX-101-treated patients (vs 3.9% of placebo-treated patients) received fewer than 6 treatment sessions owing to patient satisfaction with treatment or lack of sufficient SMF for further treatment. In both treatment groups, the incidence/severity of common injection-site adverse events declined over subsequent treatment sessions. CONCLUSIONS: Although up to 6 treatment sessions were permitted in the REFINE trials, most ATX-101-treated patients achieved an improvement in SMF within 2 to 4 treatment sessions. Level of Evidence: 3.

ATX-101 for reduction of submental fat: A phase III randomized controlled trial.

BACKGROUND: ATX-101, an injectable form of deoxycholic acid, causes adipocytolysis when injected subcutaneously into fat. OBJECTIVE: We sought to evaluate the efficacy and safety of ATX-101. METHODS: In this phase III trial (REFINE-2), adults dissatisfied with their moderate or severe submental fat (SMF) were randomized to ATX-101 or placebo. Coprimary end points, evaluated at 12 weeks after last treatment, were composite improvements of 1 or more grades and 2 or more grades in SMF observed on both the validated Clinician- and Patient-Reported SMF Rating Scales. Other end points included magnetic resonance imaging-based assessment of submental volume, assessment of psychological impact of SMF, and additional patient-reported outcomes. RESULTS: Among those treated with ATX-101 or placebo (n = 258/treatment group), 66.5% versus 22.2%, respectively, achieved a composite improvement of 1 or more grades (Mantel-Haenszel risk ratio 2.98; 95% confidence interval 2.31-3.85) and 18.6% versus 3.0% achieved a composite improvement of 2 or more grades in SMF (Mantel-Haenszel risk ratio 6.27; 95% confidence interval 2.91-13.52; P < .001 for both). Those treated with ATX-101 were more likely to achieve submental volume reduction confirmed by magnetic resonance imaging, greater reduction in psychological impact of SMF, and satisfaction with treatment (P < .001 for all). Overall, 85.7% of adverse events in the ATX-101 group and 76.9% in the placebo group were localized to the injection site. LIMITATIONS: Follow-up was limited to 44 weeks. CONCLUSION: ATX-101 is an alternative treatment for SMF reduction.

REFINE-1, a Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial With ATX-101, an Injectable Drug for Submental Fat Reduction.

BACKGROUND: ATX-101, an injectable form of deoxycholic acid, is approved in the United States and Canada for submental fat (SMF) reduction. OBJECTIVE: To report results of REFINE-1, a randomized, double-blind, placebo-controlled, Phase 3 trial investigating the efficacy and safety of ATX-101. METHODS: Subjects dissatisfied with their moderate or severe SMF received ATX-101 (2 mg/cm) or placebo. Coprimary outcome measures were composite ≥1-grade and ≥2-grade improvements in clinician-assessed and subject-assessed SMF severity using validated scales at 12 weeks after last treatment. Magnetic resonance imaging (MRI) provided an objective measure of submental volume reduction. Patient-reported outcomes were assessed. RESULTS: Among 256 ATX-101-treated and 250 placebo-treated subjects, a ≥1-grade composite response was achieved in 70.0% and 18.6%, and a ≥2-grade composite response in 13.4% and 0%, respectively (p < .001 for both). The proportion of MRI responders was more than 8 times higher with ATX-101 than placebo (46.3% vs 5.3%; p < .001). ATX-101-treated subjects reported improvement in the psychological impact of SMF and satisfaction with treatment (p < .001 for all assessments vs placebo). Of note, 55% and 75% of ATX-101-treated subjects reported 1-grade improvement in clinician-assessed SMF after 2 and 4 treatments, respectively. Adverse events (primarily localized to the injection site) were mostly mild or moderate, and transient. Marginal mandibular nerve paresis reported in 4.3% of ATX-101-treated subjects (1.0% of all ATX-101 treatment sessions) was mostly mild, transient, and resolved without sequelae. CONCLUSION: ATX-101 is a safe and efficacious, first-in-class, injectable drug for SMF reduction.

Overview of ATX-101 (Deoxycholic Acid Injection): A Nonsurgical Approach for Reduction of Submental Fat.

In 2015, ATX-101 (deoxycholic acid injection; Kybella in the United States and Belkyra in Canada; Kythera Biopharmaceuticals, Inc., Westlake Village, CA [an affiliate of Allergan plc, Dublin, Ireland]) was approved as a first-in-class injectable drug for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat. ATX-101 has been evaluated in a clinical development program that included 18 Phase 1 to 3 studies supporting the current indication. Since 2007, the toxicity and safety profiles of ATX-101 have been characterized in numerous preclinical studies, its pharmacokinetics, pharmacodynamics, and optimal treatment paradigm have been defined in multiple Phase 1 and 2 studies, and its efficacy and clinical safety have been confirmed in 4 large Phase 3 trials (2 conducted in Europe and 2 in the United States and Canada [REFINE-1 and REFINE-2]). As subcutaneous injection of deoxycholic acid has been shown to cause adipocytolysis, the reduction in submental fat achieved after ATX-101 treatment is expected to be long lasting. This prediction is confirmed by data from long-term follow-up studies of up to 4 years after last treatment with ATX-101, which demonstrate that the treatment response is maintained over time in most subjects. ATX-101 offers a durable, minimally invasive alternative to liposuction and surgery for addressing submental fullness.

Management of Patient Experience With ATX-101 (Deoxycholic Acid Injection) for Reduction of Submental Fat.

BACKGROUND: ATX-101 (deoxycholic acid injection; Kythera Biopharmaceuticals, Inc., Westlake Village, CA [an affiliate of Allergan plc, Dublin, Ireland]) was recently approved for submental fat (SMF) reduction in the United States (Kybella) and Canada (Belkyra). The pivotal trials supporting these approvals revealed that ATX-101 is associated with common injection-site treatment reactions consistent with its mechanism of action and administration procedure. OBJECTIVE: The purpose of this study was to evaluate 4 patient experience management paradigms targeting the common injection-site adverse events of pain, swelling/edema, and bruising after a single treatment session with ATX-101. METHODS: In this double-blind, parallel-group, exploratory Phase 3b study (ClinicalTrials.gov identifier: NCT02007434), subjects with moderate to severe SMF were randomized 4:1 within each paradigm to receive ATX-101 2 mg/cm or placebo. In Paradigm 1, subjects received a cold pack application to the treatment area. In Paradigm 2, in addition to cold pack application, subjects were treated with topical lidocaine and injectable lidocaine containing epinephrine. In Paradigm 3, in addition to the interventions of Paradigm 2, subjects received loratadine and ibuprofen. Subjects in Paradigm 4 received the same interventions in Paradigm 3, plus application of a chin strap. RESULTS: Eighty-three subjects were treated. In ATX-101-treated subjects, peak pain occurred within 1 to 5 minutes of treatment, with median values at these time points ranging from 21.4 to 35.7 mm on a 100-mm pain visual analog scale ("mild"). Pain ratings reduced substantially by 15 minutes; at 4 hours after injection, pain was characterized as mild tenderness or mild achiness. Compared with cold alone, treatment with topical and injectable lidocaine reduced median peak pain by 17%. Addition of ibuprofen and loratadine resulted in a total reduction in pain by 40%. Peak swelling/edema in ATX-101-treated subjects was "modest," with mean values ≤1.7 (on a 0-5 scale) across all paradigms. Swelling/edema was not substantially mitigated by the interventions, including ibuprofen, loratidine, and the use of a chin strap. Bruising associated with ATX-101 treatment was confined to the treatment area, with mean values between 1.0 and 1.4 on a 0-to-5 scale. Bruising was modestly reduced by injectable lidocaine with epinephrine. CONCLUSION: Results from this study support the safety of ATX-101 for SMF reduction, and demonstrate that pain and bruising associated with ATX-101 treatment can be mitigated by a series of simple measures.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Repeated OnabotulinumtoxinA Treatments in Subjects With Crow's Feet Lines and Glabellar Lines.

BACKGROUND: This is the third study in a Phase 3 program evaluating onabotulinumtoxinA treatment of crow's feet lines (CFL). OBJECTIVE: To assess the efficacy and safety of repeated onabotulinumtoxinA treatments of CFL alone or with glabellar lines (GL) in subjects with moderate-to-severe CFL and GL (maximum smile). MATERIALS AND METHODS: This 5-month extension of a 7-month study randomized subjects who originally received onabotulinumtoxinA 24 U (CFL only; n = 227) or 44 U (24 U for CFL + 20 U for GL; n = 260) to retreatment with the same dose. Placebo-treated subjects were rerandomized to onabotulinumtoxinA 44 U (n = 101) or placebo (n = 96). Primary efficacy end point (Day 30) was the proportion of subjects who achieved a CFL severity rating of none or mild (maximum smile) on the investigator-assessed Facial Wrinkle Scale (FWS). Additional efficacy end points and adverse events were evaluated. RESULTS: Responder rates (primary end point) were significantly greater in onabotulinumtoxinA-treated groups (24 U: 56.5%; 44 U: 63.6%; placebo: 1.1%; p < .001). Improvements on most patient-reported outcomes (PROs) favored the 44-U group over the 24-U group. Adverse events did not differ among groups; most were mild or moderate. CONCLUSION: Repeated onabotulinumtoxinA treatments significantly reduce CFL severity based on FWS and PROs. Adverse event profiles remain consistent with approved GL labeling.

Efficacy and safety of onabotulinumtoxinA for treating crow's feet lines alone or in combination with glabellar lines: a multicenter, randomized, controlled trial.

BACKGROUND: This was the second study in a Phase 3 program treating crow's feet lines (CFL) with onabotulinumtoxinA. OBJECTIVE: To evaluate the efficacy and safety of onabotulinumtoxinA treatment of CFL alone or with glabellar lines (GL). METHODS: This multicenter, double-blind, placebo-controlled, repeat treatment, 7-month study randomized subjects with moderate-to-severe CFL and GL (maximum contraction) to onabotulinumtoxinA 44 U (CFL: 24 U, GL: 20 U; n = 305), onabotulinumtoxinA 24 U (CFL: 24 U, GL: placebo; n = 306), or placebo (n = 306). Coprimary end points were investigator-assessed and subject-assessed proportion of subjects achieving a CFL Facial Wrinkle Scale Grade of 0 or 1 (maximum smile; Day 30, Cycle 1). Additional efficacy end points and safety/adverse events (AEs) were evaluated. RESULTS: All primary and secondary end points were achieved; statistically significant differences favored onabotulinumtoxinA (p < .001, all comparisons vs placebo). Investigator and subject responder rates were: CFL, 54.9% and 45.8%; CFL + GL, 59.0% and 48.5%; and placebo, 3.3% (both), respectively. Responder rates on other end points also significantly favored onabotulinumtoxinA treatments. Most AEs were mild or moderate. Two subjects discontinued: 1 serious AE unrelated to treatment (myocardial infarction) and 1 treatment-related AE (injection site pain). CONCLUSION: OnabotulinumtoxinA was effective and well tolerated for treating moderate-to-severe CFL alone or in combination with GL.

A Prospective, Nonrandomized, Open-Label Study of the Efficacy and Safety of OnabotulinumtoxinA in Adolescents with Primary Axillary Hyperhidrosis.

OBJECTIVE: To evaluate the efficacy and safety of onabotulinumtoxinA in adolescents with primary axillary hyperhidrosis. METHODS: This 52-week, multicenter, nonrandomized, open-label study was conducted in 141 adolescents ages 12 to 17 years with severe primary axillary hyperhidrosis. Patients could receive up to six treatments with onabotulinumtoxinA (50 U per axilla), with re-treatment occurring no sooner than 8 weeks after the prior treatment cycle and no later than 44 weeks after the initial treatment cycle. The primary efficacy measure was treatment response, based on self-assessed hyperhidrosis severity following the first two treatments using the 4-point Hyperhidrosis Disease Severity Scale (HDSS). Other efficacy measures included spontaneous resting sweat production and health outcomes. RESULTS: Fifty-six (38.9%) participants underwent one treatment, 59 (41.0%) underwent two, 20 (13.9%) underwent three, 6 (4.2%) underwent four, and 3 (2.1%) underwent five. OnabotulinumtoxinA significantly improved HDSS scores and decreased sweat production compared with treatment cycle baselines. Seventy-nine patients (54.9%) responded to treatment based on HDSS criteria. From 56.6% to 72.3% of patients experienced a two-grade or more improvement at 4 and 8 weeks after each of the first two treatments. The majority (79.4%-93.2%) had a 75% or greater reduction in sweat production at week 4 (treatments 1-3). The median duration of effect for responders ranged from 134 to 152 days. Using quality of life measures, health outcomes improved markedly. Eight patients (5.6%) had mild or moderate treatment-related adverse events. No unexpected safety signals were observed in this study. Neutralizing antibodies to onabotulinumtoxinA did not develop. CONCLUSION: OnabotulinumtoxinA injections provided beneficial effects in adolescents with primary axillary hyperhidrosis.

Development and validation of a photographic scale for assessment of lip fullness.

BACKGROUND: As lip augmentation becomes more popular, validated measures of lip fullness for quantification of outcomes are needed. OBJECTIVE: Develop a scale for rating lip fullness and establish its reliability and sensitivity for assessing clinically meaningful differences. METHODS: The initial Allergan Lip Fullness Scale (iLFS; a four-point photographic scale with verbal descriptions) was validated by eight physicians rating 55 live subjects during two rounds, conducted on one day. In addition, subjects performed self-evaluations. The revised Allergan Lip Fullness Scale (LFS), a five-point scale with a broader range of lip presentations, was validated by 21 clinicians in two online image rating sessions, ≥14 days apart, in which they used the LFS to rate overall, upper, and lower lip fullness of 144 3-dimensional (3D) images. Physician inter- and intra-rater agreement, subject intra-rater agreement (iLFS), and subject-physician agreement (iLFS) were evaluated. Additionally, during online rating session 1, raters ranked 38 pairs of 3D images, taken before and after lip augmentation, as "clinically different" or "not clinically different." The median LFS score difference for clinically different pairs was calculated to determine the clinically meaningful difference. RESULTS: Clinician inter- and intra-rater agreement for the iLFS and LFS was substantial to almost perfect. Subject self-assessments (iLFS) had substantial intra-rater reliability and a high level of agreement with physician assessments. Median LFS score differences for overall, upper, and lower lip fullness were 1 (mean: 0.63-0.69) for "clinically different" and 0 (mean: 0.28-0.36) for "not clinically different" image pairs; thus, clinical significance of a 1-point difference in LFS score was established. CONCLUSIONS: The LFS is a reliable instrument for physician classification of lip fullness. A 1-point score difference can detect clinically meaningful differences in lip fullness.

An interrater and intrarater reliability study of 3 photographic scales for the classification of perioral aesthetic features.

BACKGROUND: Validated aesthetic rating scales for the perioral area provide objective evaluations for clinical trials and practice. OBJECTIVE: To confirm the reliability of 3 scales for evaluating dermal filler and neurotoxin treatments of the perioral area. MATERIALS AND METHODS: Three lip-specific photographic scales were developed from standardized 2-dimensional images to evaluate Perioral Lines at Rest (POL), Oral Commissures (OCS), and Perioral Lines at Maximum Contraction (POLM) severity scales. Each 4-grade scale (none to severe) had 3 representative images per grade. Physician validators rated volunteers on each scale (2 rounds of live review). Volunteers provided 2 series of self-assessments. Physician and subject intrarater reliability were based on the comparison of round 1 and round 2 scores (mean weighted kappa coefficient). Other measures were physician interrater agreement (intraclass correlation) and subject/physician interrater agreement (Pearson correlation). RESULTS: Physician intrarater agreement was almost perfect or substantial (POL, 0.725; OCS, 0.789; POLM, 0.826). Overall, physician interrater agreement was almost perfect for all 3 scales and ranged from moderate to substantial by grade. Subject intrarater agreement and subject/physician interrater agreement were substantial. CONCLUSION: All scales demonstrated a high degree of intrarater and interrater reliability during the validation process. Physician concordance was good; subject ratings were reliable and comparable to physician assessments.

Efficacy and safety of onabotulinumtoxinA for the treatment of crows feet lines: a multicenter, randomized, controlled trial.

BACKGROUND: This study was part of a Phase 3 program treating crow's feet lines (CFL) with onabotulinumtoxinA. OBJECTIVE: To evaluate the efficacy and safety of onabotulinumtoxinA treatment of CFL. METHODS: This multicenter, double-blind, placebo-controlled, 5-month study randomized subjects with moderate-to-severe CFL (maximum smile) to onabotulinumtoxinA (24 U; n = 222) or placebo (n = 223). Investigators and subjects assessed CFL severity (maximum smile and rest) using the 4-grade Facial Wrinkle Scale (FWS). Co-primary end points were investigator- and subject-assessed proportion of subjects achieving a CFL FWS grade of 0 (none) or 1 (mild) at maximum smile (Day 30). Additional efficacy end points, patient-reported outcomes, and safety/adverse events (AEs) were evaluated. RESULTS: All primary and secondary end points were achieved; statistically significant differences favored onabotulinumtoxinA (p < .001, all comparisons vs placebo). Co-primary responder rates were 66.7% compared with 6.7% for investigator-assessed and 58.1% compared with 5.4% for subject-assessed response (onabotulinumtoxinA group and placebo, respectively; p < .001). A significantly greater proportion of the onabotulinumtoxinA group than placebo group achieved a 1 grade or greater improvement on the FWS (maximum smile and rest assessed by both the investigator and subject; all time points; p < .001). Most AEs were mild or moderate and did not result in discontinuations. CONCLUSION: Treatment of moderate-to-severe CFL with onabotulinumtoxinA was effective and well tolerated.

Juvederm ultra for lip enhancement: an open-label, multicenter study.

BACKGROUND: Juvéderm Ultra injectable gel (Allergan, Inc, Irvine, California) is approved in the United States to treat moderate to severe wrinkles and folds, such as nasolabial folds. It is also used to enhance the appearance of the lips. OBJECTIVES: The authors evaluated the safety and effectiveness of Juvéderm Ultra injectable gel for lip enhancement and assessed the utility of 3 new lip-specific effectiveness scales. METHODS: In this multicenter study, 50 subjects received lip enhancement with Juvéderm Ultra injectable gel. The subjects were observed closely by the treating investigator and results were evaluated by a blinded independent rater and by subject self-assessment for up to 48 weeks to determine the durability of the effects. A validated lip fullness scale (LFS) was used for analysis. Treatment satisfaction was assessed by investigators and subjects using an 11-point scale. RESULTS: At week 12, 71% of subjects had achieved their goals for lip fullness and had maintained improvement of at least 1 grade on the LFS, which greatly exceeded the a priori criterion of 40% for success. At week 24, improvement in lip fullness was still present for 56% of subjects. Satisfaction and goal achievement exceeded 90% for subjects as well as investigators. Common side effects were predominantly mild or moderate in intensity and resolved within 1 week in the majority of subjects. CONCLUSIONS: Juvéderm Ultra injectable gel is safe and effective for lip enhancement. Scales for assessing lip fullness provide an objective method to determine the effectiveness of treatment.

Patient-reported outcomes of bimatoprost for eyelash growth: results from a randomized, double-masked, vehicle-controlled, parallel-group study.

BACKGROUND: Hypotrichosis of the eyelashes may negatively influence an individual's self-perception and appearance. Assessing the impact of treatment from a patient's perspective may be particularly relevant in trials of aesthetic agents. Once-daily dermal (topically applied) administration of bimatoprost ophthalmic solution 0.03% has been associated with increased eyelash prominence (ie, length, thickness, darkness). OBJECTIVES: The authors assess patient-reported outcomes (PRO) after treatment with bimatoprost for hypotrichosis of the eyelashes. METHODS: In this multicenter, double-masked, randomized, vehicle-controlled, parallel clinical trial, 4 PRO questionnaires were distributed to 278 patients (bimatoprost [n = 137] and vehicle [n = 141]). The primary PRO questionnaire was the 23-item Eyelash Satisfaction Questionnaire (ESQ), which measured satisfaction in 3 domains: length, fullness, and overall satisfaction (LFOS); confidence, attractiveness, and professionalism (CAP); and impact on daily routine (DR). RESULTS: By week 16, the bimatoprost group reported significantly greater improvements from baseline on all ESQ items (P ≤ .0433). These improvements were sustained through the 4-week posttreatment study visit. Patient satisfaction was significantly greater in the bimatoprost group than in the vehicle group for all 3 domains: LFOS (weeks 8-20; P ≤ .0052), CAP (weeks 12-20; P < .0001), and DR (weeks 16 and 20; P ≤ .01). CONCLUSIONS: The bimatoprost group reported significantly greater levels of positive patient outcomes and satisfaction than the vehicle group across all 23 questions and all 3 domains of the primary PRO questionnaire. These results support the effectiveness, as measured by objective measures and PRO, of once-daily bimatoprost ophthalmic solution 0.03% at producing more prominent eyelashes in adults.

Eyelash growth in subjects treated with bimatoprost: a multicenter, randomized, double-masked, vehicle-controlled, parallel-group study.

BACKGROUND: Bimatoprost 0.03% is associated with increased growth and prominence of eyelashes. OBJECTIVE: We sought to compare the safety and efficacy of once-daily bimatoprost 0.03% versus vehicle in increasing eyelash length, thickness, and darkness after topical administration to upper eyelid margins. METHODS: In this 5-month study, subjects were randomized to receive once-daily bimatoprost 0.03% (n = 137) or vehicle (n = 141). The primary end point was eyelash prominence assessed by the investigator global eyelash assessment scale. Secondary efficacy measures included eyelash length, thickness, and darkness measured by digital image analysis and patient-reported outcomes. Safety data included adverse event monitoring and ophthalmic examinations. RESULTS: A higher percentage of subjects treated with bimatoprost 0.03% (78.1%) versus vehicle (18.4%) demonstrated at least a 1-grade increase in global eyelash assessment score at week 16 (P < .0001). Subjects in the bimatoprost 0.03% group also had statistically significantly greater increases in eyelash length, thickness, and darkness (P < .0001) than those in the vehicle group. For adverse events, only conjunctival hyperemia occurred at a statistically significant higher incidence rate in the bimatoprost 0.03% versus the vehicle group (P = .03). LIMITATIONS: Short-term duration of the trial was a limitation; black subjects were not enrolled secondary to technical requirements of digital image analysis. CONCLUSION: Bimatoprost 0.03% was found to be effective at enhancing eyelashes in adults with a very good safety profile.

OnabotulinumtoxinA: a meta-analysis of duration of effect in the treatment of glabellar lines.

BACKGROUND: Duration of effect of aesthetic treatments with botulinum toxin potentially influences subject satisfaction, treatment frequency, and annual costs, but quantitative outcomes for measuring duration of effect and correlations with subject satisfaction have yet to be fully elucidated. METHODS AND MATERIALS: Phase III clinical trials with similar designs were identified and their data pooled to ascertain duration of clinical effect of onabotulinumtoxinA in glabellar muscles. Duration was calculated using the Kaplan-Meier method for investigator-rated Facial Wrinkle scale (FWS) scores and subject global assessment (SGA) of glabellar lines. Responders were determined according to FWS score at maximum contraction and at repose 30 days after injection. RESULTS: Data from four trials with 621 onabotulinumtoxinA-treated (20 U) subjects were analyzed, 523 of these (84.2%) were identified as day-30 responders on the FWS at maximum contraction. Pooled median duration of effect for day-30 responders was 120 days for FWS at maximum contraction and 131 days for FWS at repose. Higher day 30 SGA scores were correlated with a greater duration of effect on dynamic, but not static lines. CONCLUSION: Treatment of glabellar lines with 20 U of onabotulinumtoxinA resulted in sustained clinical benefit for 4 months in more than 50% of responders; subject satisfaction increased with duration of effect.

Dose response with onabotulinumtoxinA for post-stroke spasticity: a pooled data analysis.

Clinical trials demonstrate that onabotulinumtoxinA reduces upper limb post-stroke spasticity, with therapeutic response influenced by injected dose. Individual studies provide limited insight regarding muscle group-specific dose-response relationships. Our objective was to characterize dose-response relationships between onabotulinumtoxinA and muscle tone in specific upper limb muscles. Individual patient data from seven multicenter, randomized, double-blind, placebo-controlled trials were pooled. Of 544 post-stroke patients enrolled, 362 received onabotulinumtoxinA and 182 received placebo, injected into the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), and/or biceps brachii (BB). Ashworth Scale score change at week 6 (AshworthCBL) was the primary outcome measure for muscle tone. For a broader analysis of response, AshworthCBL/onabotulinumtoxinA dosage relationships were characterized using three techniques: (1) AshworthCBL plotted as a function of onabotulinumtoxinA dose in Units (U) [dose-response curve]; (2) mean AshworthCBL per onabotulinumtoxinA dose depicting the responses seen with specific dose injection clusters/groups for each specific muscle group; and (3) onabotulinumtoxinA dose estimated to produce a mean 1-point decrease in AshworthCBL as an indicator of clinically meaningful benefit of treatment. Increasing onabotulinumtoxinA doses produced greater AshworthCBLs (muscle tone improvements). The maximal week 6 response (E(max)) model indicated a saturating dose-response relationship, with mean E(max) AshworthCBL values of -1.48, -1.48, -0.63, -0.77, and -0.61 in the FCR, FCU, FDS, FDP, and BB, respectively. OnabotulinumtoxinA doses estimated to produce a mean 1-point decrease in AshworthCBL were: 22.5U, 18.4U, 66.3U, 42.5U in the FCR, FCU, FDS, and FDP, respectively, and not determinable in the BB. These analyses demonstrate a saturating effect of greater muscle tone improvements with increasing onabotulinumtoxinA doses in post-stroke spasticity patients. These findings suggest potentially effective onabotulinumtoxinA doses in selected muscle groups in this study population.

Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications.

This meta-analysis evaluated the frequency of neutralizing antibody (nAb) conversion with onabotulinumtoxinA (BOTOX®; Allergan) across five studied indications. The analysis was based on large, controlled or prospective, open-label trials (durations 4 months to ≥2 years). Serum samples were analyzed for nAbs using the Mouse Protection Assay. Subjects who were antibody negative at baseline and had at least one analyzable postbaseline antibody assay result were included. The 16 clinical studies included 3,006 subjects; of these, 2,240 met the inclusion criteria for this analysis. Subjects received 1-15 treatments (mean 3.8 treatments) with onabotulinumtoxinA. Total doses per treatment cycle ranged from 10 or 20 units in glabellar lines to 20-500 units in cervical dystonia. The numbers of subjects who converted from an antibody-negative status at baseline to antibody-positive status at any post-treatment time point were: cervical dystonia 4/312 (1.28%), glabellar lines 2/718 (0.28%), overactive bladder 0/22 (0%), post-stroke spasticity 1/317 (0.32%), and primary axillary hyperhidrosis 4/871 (0.46%). Across all indications, 11/2,240 subjects (0.49%) converted from antibody negative at baseline to positive at one or more post-treatment time points, but only three subjects became clinically unresponsive to onabotulinumtoxinA at some point following a positive assay. Based on these large trials, the frequency of antibody conversion after onabotulinumtoxinA treatment is very low, and infrequently leads to loss of efficacy. © 2010 Movement Disorder Society.

Visual screening for malignant melanoma: a cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of various melanoma screening strategies proposed in the United States. DESIGN: We developed a computer simulation Markov model to evaluate alternative melanoma screening strategies. PARTICIPANTS: Hypothetical cohort of the general population and siblings of patients with melanoma. Intervention We considered the following 4 strategies: background screening only, and screening 1 time, every 2 years, and annually, all beginning at age 50 years. Prevalence, incidence, and mortality data were taken from the Surveillance, Epidemiology, and End Results Program. Sibling risk, recurrence rates, and treatment costs were taken from the literature. MAIN OUTCOME MEASURES: Outcomes included life expectancy, quality-adjusted life expectancy, and lifetime costs. Cost-effectiveness ratios were in dollars per quality-adjusted life year (US dollars/QALY) gained. RESULTS: In the general population, screening 1 time, every 2 years, and annually saved 1.6, 4.4, and 5.2 QALYs per 1000 persons screened, with incremental cost-effectiveness ratios of US dollars 10,100/QALY, US dollars 80,700/QALY, and US dollars 586,800/QALY, respectively. In siblings of patients with melanoma (relative risk, 2.24 compared with the general population), 1-time, every-2-years, and annual screenings saved 3.6, 9.8, and 11.4 QALYs per 1000 persons screened, with incremental cost-effectiveness ratios of US dollars 4000/QALY, US dollars 35,500/QALY, and US dollars 257,800/QALY, respectively. In higher risk siblings of patients with melanoma (relative risk, 5.56), screening was more cost-effective. Results were most sensitive to screening cost, melanoma progression rate, and specificity of visual screening. CONCLUSIONS: One-time melanoma screening of the general population older than 50 years is very cost-effective compared with other cancer screening programs in the United States. Screening every 2 years in siblings of patients with melanoma is also cost-effective.

The impact of upper facial lines and psychological impact of crow's feet lines: content validation of the Facial Line Outcomes (FLO-11) Questionnaire.

BACKGROUND: Treatments for upper facial lines (UFL), the most visible sign of aging, are of interest to patients and clinicians alike. Patient-reported outcomes (PROs) are valuable in evaluating the impact of such treatments; however, regulatory recommendations have stipulated that the patient perspective be central in developing these assessments. OBJECTIVES: (1) To evaluate the content validity of the Facial Lines Outcomes Questionnaire, a PRO instrument developed to assess upper facial line impacts, according to the regulatory guidance of the United States Food and Drug Administration and (2) assess whether it adequately measures the psychological impacts associated with crow's feet lines (CFL) (lateral canthal lines) from the patient perspective. METHODS: Two patient groups participated in face-to-face qualitative interviews. One group included patients with UFL (Group 1, n = 25 interviews), and the other included patients specifically with CFL (Group 2, n = 41 interviews). Each interview consisted of a concept elicitation and cognitive debriefing phase. RESULTS: Interviews with both groups elicited all key concepts of the instrument, including "bothered by facial lines"; "looking older"; "looking less attractive"; and looking "tired," "stressed," or "angry." Most Group 2 patients (n = 35, 85%) agreed that the instrument adequately assessed the psychological impacts associated with CFL. During cognitive debriefing, the majority of patients in both groups agreed the instrument was understandable, comprehensive, and easy to complete. CONCLUSIONS: The Facial Line Outcomes Questionnaire is an appropriate and valid tool to assess the impact of UFL and the psychological impacts associated with CFL.

Long-term safety evaluation of bimatoprost ophthalmic solution 0.03%: a pooled analysis of six double-masked, randomized, active-controlled clinical trials.

BACKGROUND: Bimatoprost ophthalmic solution 0.03% was approved in the US for reducing intraoccular pressure (IOP) based on two double-masked, active-controlled clinical trials. Four additional long-term studies (≥12 months) were conducted; however, the aggregate safety profile of the six studies has not been reported. METHODS: Adverse events (AEs) were pooled from six double-masked, active-controlled, long-term clinical trials in which subjects received bimatoprost 0.03% once daily (QD) or twice daily (BID) as an eyedrop. AE terms were converted to MedDRA (V.11.0) Preferred Terms and analyzed. RESULTS: In total, 1409 patients received more than one dose of bimatoprost 0.03% QD or BID. Most AEs were mild in severity and reported by 86.7% (QD) and 94.8% (BID) of subjects (≤12 months of treatment). AEs reported through month 12 (aggregate incidence of ≥5%) were conjunctival hyperemia, increased eyelash growth, eye pruritus, periocular skin hyperpigmentation, eye irritation, dry eye, and hypertrichosis. AE onset was generally reported within four months of treatment. The cumulative incidence of common AEs in the QD treatment group at 24-48 months was similar to that measured at 12 months of treatment. CONCLUSION: Bimatoprost 0.03% has a favorable safety and tolerability profile as characterized by six long-term studies. Common AEs were due to the known pharmacological activity of bimatoprost and reversible with treatment cessation.