Treatment of glabellar lines with Botox (onabotulinumtoxinA): Development, insights, and impact.

OnabotulinumtoxinA is an injectable medication that produces muscle relaxation through local chemical denervation at the neuromuscular junction. Discovery of onabotulinumtoxinA's aesthetic benefits occurred serendipitously in the 1980s at the intersection of several medical disciplines, including ophthalmology, neurology, otolaryngology, and dermatology. Patients receiving onabotulinumtoxinA for blepharospasm, hemifacial spasm, and dystonia noticed their periorbital wrinkles disappearing, particularly frown lines between the eyebrows called glabellar lines (GL). Aesthetic use of onabotulinumtoxinA necessitated rigorous training programs and vigilant monitoring by Allergan. Approval for the GL indication was based on 2 similarly designed, double-blind, randomized, multicenter clinical studies. Subjects with moderate to severe GL receiving onabotulinumtoxinA achieved significantly greater improvement in GL severity than those receiving placebo. In subsequent studies, more than 80% of subjects were satisfied with onabotulinumtoxinA treatment through day 60, and many reported looking approximately 4 years younger at weeks 4 and 12 than at baseline. OnabotulinumtoxinA has a rapid onset of action, and peak effect occurs between 30 and 60 days. The median duration of response for dynamic GL in the initial studies was 120 days and response progressively improved with subsequent treatments. OnabotulinumtoxinA was well tolerated, and the 2 most common adverse events, headache and blepharoptosis, tended to decrease in frequency with repeat treatment. The novel use of onabotulinumtoxinA for treating GL was an important step in addressing the clinical need for a noninvasive, straightforward, office-based procedure for facial lines that also left patients extremely satisfied with its treatment effects and represented the beginning of its widespread use for numerous aesthetic indications.

Treatment of hyperhidrosis with Botox (onabotulinumtoxinA): Development, insights, and impact.

Hyperhidrosis (chronic excessive sweating) may substantially affect an individual's emotional and social well-being. Therapies available before onabotulinumtoxinA were generally topical, with limited effectiveness, application-site skin reactions, and frequent, time-consuming treatments. Intradermal injection of onabotulinumtoxinA to treat sweat glands arose as a novel therapeutic approach. To develop this treatment, appropriate dosing needed to be established, and training on administration was required. Further, no previous scale existed to measure the effects of hyperhidrosis on patients' lives, leading Allergan to develop and validate the 4-point Hyperhidrosis Disease Severity Scale (HDSS), which measures the disease's impact on daily activities. The onabotulinumtoxinA clinical development program for hyperhidrosis included 2 double-blind, placebo-controlled pivotal trials, immunogenicity studies, long-term studies of safety and efficacy, and quality of life assessments. In Europe and North America, the primary efficacy measures were, respectively, axillary sweat production measured gravimetrically and HDSS improvement. Compared with placebo, onabotulinumtoxinA treatment significantly reduced axillary sweat production and axillary hyperhidrosis severity, as measured by a 2-point or greater reduction on the HDSS. The effects of onabotulinumtoxinA occurred rapidly, within 1 week after injection, and lasted ≥6 months. Treatment with onabotulinumtoxinA was associated with significant quality of life improvements based on Short Form-12 physical and mental component scores. The Hyperhidrosis Impact Questionnaire also indicated greater treatment satisfaction, reduced negative impact on aspects of daily life, and improved emotional well-being with onabotulinumtoxinA versus placebo. The clinical development program and subsequent clinical experience showed that onabotulinumtoxinA treatment for hyperhidrosis was well tolerated with no new safety signals, and led to greater disease awareness.

LongITools: Dynamic longitudinal exposome trajectories in cardiovascular and metabolic noncommunicable diseases.

The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our "modern" postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases.

OnabotulinumtoxinA treatment of mild glabellar lines in repose.

BACKGROUND: OnabotulinumtoxinA is an established treatment for glabellar frown lines, but its effects on lines at repose are less well documented. OBJECTIVE: To assess the effect of onabotulinumtoxinA on elimination of mild lines at repose. METHODS: Data from two randomized, double-blind, placebo-controlled studies were included. Elimination of mild lines at repose was defined as change from mild to none on the Facial Wrinkle Scale. RESULTS: Analysis included 183 participants who received 20 U of onabotulinumtoxinA and 64 participants who received placebo, all with mild lines at repose at baseline. Participants were evaluated 7, 30, 60, 90, and 120 days posttreatment. Compared to placebo, onabotulinumtoxinA-treated participants were significantly more likely to have their lines at repose eliminated at each study day; [odds ratios ranged from 42.7 (95% confidence interval (CI)=12.9-141.9) at day 30 to 4.9 (95% CI=2.2-10.8) at day 120 (p<.0001 at each day)]. The highest response rate was observed at day 30 (68%). CONCLUSION: OnabotulinumtoxinA has demonstrated the ability to eliminate mild glabellar lines at repose for a significant number of patients. This effect, albeit more subtle than the effect on dynamic or more severe glabellar lines, may be an important treatment goal for patients who seek a smoother appearance at repose.

Safety and tolerability of onabotulinumtoxinA in the treatment of facial lines: a meta-analysis of individual patient data from global clinical registration studies in 1678 participants.

BACKGROUND: OnabotulinumtoxinA for the treatment of facial lines is a widely used cosmetic medical procedure and, as such, the safety and tolerability profile is of interest to health care providers and patients. Based on data from individual studies that were conducted according to regulatory guidelines to provide adequate safety and efficacy data to support product licensure (registration studies), the overall benefit:risk profile of onabotulinumtoxinA for facial lines has been favorable. OBJECTIVE: Our objective was to increase statistical power through meta-analysis to detect treatment group differences in adverse event (AE) incidence that may not have been evident in individual registration studies. METHODS: Individual participant data (n = 1678) were from 6 randomized, double-blind, placebo-controlled and 3 open-label studies. Two double-blind, placebo-controlled studies were for lateral canthal lines (3-18 U/side) and all others were for glabellar lines (10 or 20 U). Doses used reflect global product labeling in countries where licensed. RESULTS: Participant population was non-Hispanic white (43%) or Asian (52%) and predominantly female (88%). In double-blind, placebo-controlled studies, overall AE incidence did not significantly differ by treatment group (onabotulinumtoxinA vs placebo). The only individual AEs with significantly greater incidence in the onabotulinumtoxinA group were eyelid sensory disorder (2.5% vs 0.3%, P = .004; verbatim phrases "tight," "pressured," "heavy," "drooping feeling," "feeling of droopiness") and eyelid ptosis (1.8% vs 0%, P = .02), both present only in glabellar studies. Overall treatment-related (per investigator) AE incidence was greater in the onabotulinumtoxinA group versus placebo (24% vs 16%, P = .005), and treatment-related eyelid edema was an additional AE with significantly higher incidence in the onabotulinumtoxinA group versus placebo (P = .04). Incidence of all 3 of these AEs significantly decreased as number of treatment cycles increased. Eyelid sensory disorder and eyelid edema were more common in Asian participants. Acne, injection site pruritus, oral herpes, rash, lower respiratory tract infection, dental caries, and eye pain were significantly more common in placebo-treated compared with onabotulinumtoxinA-treated participants. Serious AE incidence did not significantly differ by treatment (onabotulinumtoxinA vs placebo) and no serious AEs were treatment related. There were no symptoms of weakness remote to the injection site or related to the central nervous system. LIMITATIONS: Limitations included: (1) highly visible efficacy of onabotulinumtoxinA may have resulted in reporting bias; (2) reliance on participant intervisit recall; (3) a relatively short follow-up period (1 year); (4) conclusions are based solely on the doses analyzed (ie, those used in the respective trials); and (5) exclusion of patients with severe medical disease in registration studies. CONCLUSION: This meta-analysis confirms the safety and tolerability of onabotulinumtoxinA for glabellar and lateral canthal lines, at the doses studied, based on the most comprehensive controlled safety analysis of onabotulinumtoxinA performed to date. The AEs observed were generally mild to moderate; most treatment-related AEs were related either to physical injection of product or local pharmacologic effects. Even with the increased statistical power of a large sample size, no new onabotulinumtoxinA-associated AEs emerged.

Botulinum toxin type A in the treatment of primary axillary hyperhidrosis: a 52-week multicenter double-blind, randomized, placebo-controlled study of efficacy and safety.

BACKGROUND: The long-term effects of botulinum toxin type A (BoNTA) on the global impairment associated with severe primary axillary hyperhidrosis have not been comprehensively assessed relative to placebo. OBJECTIVE: To assess the efficacy and safety of 2 dosages of BoNTA compared with placebo in subjects with primary axillary hyperhidrosis. METHODS: Subjects (N = 322) were randomized to the use of BoNTA (75 U or 50 U/axilla) or placebo in this 52-week, multicenter, double-blind study. RESULTS: BoNTA treatment significantly reduced daily activity limitations at 4 weeks after injection. A 2-point improvement on the 4-point Hyperhidrosis Disease Severity Scale (HDSS) was reported in 75% of subjects in the 75-U and 50-U BoNTA groups and in 25% of the placebo group (P < .001). Improvements in HDSS scores were corroborated by gravimetric results. The median duration of effect was 197 days, 205 days, and 96 days in the 75-U, 50-U, and placebo groups, respectively. BoNTA was well tolerated. LIMITATIONS: The effect of total surface area involvement on treatment efficacy was not evaluated. CONCLUSION: BoNTA treatment effectively reduces the symptoms of primary axillary hyperhidrosis and is well tolerated.

Double-blind, randomized, placebo-controlled, dose-response study of the safety and efficacy of botulinum toxin type A in subjects with crow's feet.

BACKGROUND: Published evidence suggests that botulinum toxin type A (BTX-A) is an effective treatment for crow's feet. However, few dose-ranging studies have been performed. OBJECTIVES: To assess the safety and efficacy of a single treatment with one of four doses of BTX-A (Botox/Vistabel, Allergan Inc) compared with placebo for the improvement of crow's feet. METHODS: Subjects received a single bilateral treatment of 18, 12, 6, or 3 U of BTX-A or placebo injected into the lateral aspect of the orbicularis oculi muscle (parallel-group, double-blind design). Investigators and subjects rated crow's feet severity at maximum smile on day 7 and at 30-day intervals from days 30 to 180. RESULTS: As observed by both investigators and subjects, all doses of BTX-A resulted in improvements in crow's feet severity when compared with placebo. A dose-dependent treatment effect for efficacy was observed, with higher doses having an increased magnitude and duration of effect. However, a clear differentiation between the 18 U and 12 U doses was not apparent. Few adverse events were reported, with no statistically significant differences between BTX-A and placebo in the incidence of subjects experiencing adverse events. CONCLUSION: BTX-A is safe and effective in decreasing the severity of crow's feet, with 12 U per side suggested as the most appropriate dose.

Double-blind, placebo-controlled study of the safety and efficacy of botulinum toxin type A for patients with glabellar lines.

The objective of this study was to evaluate the efficacy and safety of botulinum toxin type A for the treatment of glabellar lines. Patients with moderate or severe glabellar lines at maximal frown received intramuscular injections of placebo or 20 U of botulinum toxin type A (Botox; Allergan, Inc., Irvine, Calif.) distributed among five injection sites (one in the procerus muscle and two in each corrugator supercilii). Follow-up assessments were performed at 7, 30, 60, 90, and 120 days after injections. Efficacy measures were the physician's rating of glabellar line severity at maximal frown and at rest (none, mild, moderate, or severe) and the patient's global assessment of changes in glabellar lines, from +4 (100 percent better) to -4 (100 percent worse). A total of 273 patients were enrolled (botulinum toxin, 202 patients; placebo, 71 patients). All except five patients (botulinum toxin, two patients; placebo, three patients) completed the study. For the physician's rating at maximal frown, the responder rate (percentage of patients with severity ratings of none or mild in follow-up evaluations) for the botulinum toxin group peaked at 77 percent at day 30 and was significantly greater than that for the placebo group at every follow-up visit (p < 0.001). For the patient's assessment, the responder rate (percentage of patients with scores of +2 or more) for the botulinum toxin group peaked at 89 percent at day 30 and was significantly greater than that for the placebo group at every follow-up visit (p < 0.001). Rates of adverse events were similar for the two groups. The only adverse event with an incidence of >/=5 percent was headache (botulinum toxin, 11 percent; placebo, 20 percent). The incidence of blepharoptosis was 1 percent for the botulinum toxin group. Botulinum toxin type A was remarkably safe and effective in reducing glabellar lines.

A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines.

BACKGROUND: Botulinum toxin type A (BTX-A) is widely used for facial esthetics but is incompletely studied. OBJECTIVE: This study was conducted to evaluate the efficacy and safety of BTX-A treatment of glabellar lines. METHODS: Patients with moderate to severe glabellar lines at maximum frown received intramuscular injections of 20 U BTX-A (BOTOX, Allergan, Inc, Irvine, Calif) or placebo into 5 glabellar sites. Patients were followed up for 120 days after injection. Outcome measures were physician rating of glabellar line severity at maximum frown and rest, patient assessment of improvement, and vital sign and adverse event monitoring. RESULTS: Two hundred sixty-four patients were enrolled (BTX-A: 203, placebo: 61). There was a significantly greater reduction in glabellar line severity with BTX-A than with placebo (all measures, every follow-up visit; P <.022). The effect was maintained for many patients through day 120. There was a low occurrence (5.4%) of mostly mild blepharoptosis in the BTX-A group. CONCLUSION: BTX-A injections are safe and effective in reducing the severity of glabellar lines.