Frederick C. Beddingfield

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.

Effectiveness of Juvéderm Ultra Plus dermal filler in the treatment of severe nasolabial folds.

Background: With the baby boomer generation firmly ensconced in middle age and the ubiquity of botulinum toxin type A, nonsurgical facial rejuvenation is becoming increasingly prevalent. As this generation continues to age, products with greater therapeutic power to correct aging changes will be in growing demand. Methods: A multicenter, double-blind, randomized, within-subject, controlled study was conducted comparing Juvéderm Ultra Plus hyaluronic acid filler with bovine collagen. A subset of subjects classified as having treatment for severe nasolabial folds is presented in this article. Subjects received Juvéderm Ultra Plus in one severe nasolabial fold and Zyplast collagen in the other nasolabial fold; up to two touch-up treatments were allowed at 2-week intervals. Nasolabial fold severity was evaluated every 4 weeks for 24 weeks using a five-point scale. Treatment site reactions and adverse events were also recorded. A complimentary treatment was offered at the end of the trial, with effectiveness evaluations just before retreatment and up to 48 weeks after repeated treatment for a subset of subjects. Results: Of the 87 subjects, most were female Caucasians, but all Fitzpatrick skin types were represented (36 percent types IV through VI). At 24 weeks, 96 percent of nasolabial folds treated with Juvéderm had maintained clinically significant correction, and 81 percent maintained the correction for 1 year or more. Results were similar for those subjects with follow-up through 48 weeks after repeated treatment. The median volume required for repeated treatment with Juvéderm was significantly less than that for initial treatment (0.7 ml versus 1.6 ml). Conclusion: Juvéderm Ultra Plus provides correction of severe nasolabial folds through 1 year or more.

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.

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 (Emax) model indicated a saturating dose–response relationship, with mean Emax 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.

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.

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.

Factors associated with prolongation of transport times of emergency pediatric patients requiring transfer to a tertiary care center

Purpose: The purpose of this study was to determine factors associated with longer times to transport of emergency pediatric patients requiring tertiary care. Design: Retrospective case series. Setting: Emergency pediatric transport service. Participants: Infants and children transported by the transport service at the University of North Carolina Hospitals at Chapel Hill from January 1, 1988, to December 31, 1990. Main measurements: The time-to-request, the time from patient arrival at the referring hospital to the time when the request for transfer was received, and the ground time, defined as the time between the transport teams arrival at the referring hospital and their departure, were recorded for each transported patient. Results: Three hundred consecutive children 0 to 16 years (61 % male) were transferred. Time-to-request was shorter for trauma patients (median 62 minutes, quartiles 29 and 153 minutes) than for medical patients (median 172 minutes, quartiles 83 and 508 minutes) (P=0.0001). Infants, children, and adolescents had similar times-to-request of 147 minutes, 129 minutes, and 128 minutes, respectively (P=0.91). Increased ground times were associated with diagnosis category (median of 40 minutes for medical patients vs 29 minutes for trauma patients) (P=0.0001), with younger age (median of 46 minutes for infants, 35 minutes for children, and 28 minutes for adolescents) (P=0.0001), and with the performance of major procedures (median of 35 minutes if no procedures were performed, 38 minutes if one procedure was performed, and 54 minutes if two procedures were performed) (P=0.039). After the transport team arrived, 13% (40/300) of patients required at least one major procedure prior to transport. Conclusions: Increased time-to-request for patients with medical diagnoses, increased ground times for younger patients and patients with medical diagnoses, and failure to perform necessary procedures contribute to a prolongation of the time-to-transport of emergency pediatric patients. The magnitude of the impact of these longer transport times on outcome is unknown.

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 crows 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 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 crows 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.

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.