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Abstract It is important for patients that treatments for diabetes not increase cardiovascular (CV) risk. The objective of this analysis was to examine retrospectively the CV safety of exenatide BID, a GLP-1 receptor agonist approved for treating hyperglycemia in patients with type 2 diabetes not adequately controlled with diet and exercise. Individual participant data was pooled to assess the relative risk (RR) of CV events with exenatide BID versus a pooled comparator (PC) group treated with either placebo or insulin from 12 controlled, randomized, clinical trials ranging from 12-52 weeks. Mean baseline values for HbA1c (8.33-8.38%), BMI (31.3-31.5 kg/m2), and duration of diabetes (8 y) were similar between groups. Trials included patients with histories of microvascular and/or macrovascular disease. Customized primary major adverse CV events (MACE) included stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures. The Primary MACE RR (0.7; 95% CI 0.38, 1.31), calculated by the Mantel-Haenszel method (stratified by study), suggested that exenatide use (vs. PC) did not increase CV risk; this result was consistent across multiple analytic methods. Because the trials were not designed to assess CV outcomes, events were identified retrospectively from a list of preferred terms by physicians blinded to treatment. Other limitations included the low number of CV events, the short duration of trials (≤1 y), and a single active comparator (insulin). The results of these analyses are consistent with those of a recent retrospective analysis of a large insurance database that found that patients treated with exenatide twice daily were less likely to have a CV event than were patients treated with other glucose-lowering therapies. Keywords: GLP-1 receptor agonist, diabetes, cardiovascular safety

Background: This pooled analysis of randomized controlled studies investigated the safety and efficacy of onabotulinumtoxinA in male and female patients with overactive bladder (OAB). Methods: Data were pooled from four similarly designed trials in North America and Europe. Adults with idiopathic OAB for ≥6 months inadequately managed by at least one anticholinergic were randomized 1:1 or 2:1 to receive onabotulinumtoxinA 100 U or matched placebo in Cycle 1 and could request open‐label retreatment with onabotulinumtoxinA 100 U at ≥12 weeks. Efficacy outcomes at Week 12 included the primary endpoint of mean urinary incontinence (UI) episodes per day and other variables, such as the proportion of patients with ≥50% reduction in daily UI episodes. Safety was assessed by monitoring treatment‐emergent adverse events (TEAEs). Analyses by sex were descriptive. Males were further analyzed by benign prostatic hyperplasia (BPH) diagnosis status. Results: In the pooled population (N = 1564), there were 194 males (12.4%) and 1370 females (87.6%). Mean number of baseline UI episodes per day was 4.9 in males and 5.5 in females. At Week 12, numerically greater mean reductions from baseline in number of daily UI episodes were observed with the onabotulinumtoxinA 100 U group (females: −3.0; males: −2.2) versus placebo (females: −1.1; males: −1.3). Achievement of ≥50% reduction in daily UI episodes was numerically greater with onabotulinumtoxinA 100 U (females: 64.8%; males: 61.2%) versus placebo (females: 30.6%; males: 44.8%), and numerically higher in males without BPH (onabotulinumtoxinA: 65.1%; placebo: 50.9%) versus with BPH (onabotulinumtoxinA: 54.3%; placebo: 36.6%). A total of 34.7% of males and 39.4% of females experienced at least one TEAE in the first 12 weeks during treatment Cycle 1. Urinary tract infection rate was 13.1% in females and 4.2% in males; incidence of hematuria was 6.8% in males and 1.1% in females. Incidence of urinary retention (defined as incomplete emptying, requiring catheterization) was 2.7% in females and 4.7% in males. Conclusion: OnabotulinumtoxinA 100 U was efficacious and well tolerated in men and women with OAB, including in males with and without BPH. No new safety findings were identified when data were analyzed by sex. [ABSTRACT FROM AUTHOR]

OnabotulinumtoxinA (onabotA) is approved in the US for 12 therapeutic indications. Real-world data on onabotA multi-indication use are limited, often leading to delayed or reduced treatment. This study provides real-world evidence on the safety of onabotA when treating multiple indications concomitantly. SYNCHRONIZE was a multicenter, retrospective, chart-review study evaluating onabotA's safety for adults treated for ≥2 therapeutic indications within a 3-month period. The primary outcome was treatment-emergent adverse events (TEAEs) within 6 months post-treatment. A total of 279 patients were included. The most common concomitant indications treated were cervical dystonia and chronic migraine (43.4%). The average 3-month cumulative dose for multiple indications was 282.2 U. The treatment interval for multiple indications was ≤24 h for most patients (62.4%). Overall, 28.7% of patients reported ≥1 TEAE with no apparent trends in TEAEs and dose interval or cumulative dose. Reported TEAEs included UTI (5.7%), neck pain (5.0%), and headache (4.3%). No patient had a lack of effect according to clinical objective measurements. SYNCHRONIZE described the real-world safety of onabotA for patients treated concomitantly for ≥2 indications within a 3-month period. TEAEs were generally consistent with the known safety profiles of individual indications. No new safety signals were identified). [ABSTRACT FROM AUTHOR]

Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles. The NAb formation at baseline and post-treatment was tested and examined for impact on clinical safety and efficacy. Overall, 27 of the 5876 evaluable subjects (0.5%) developed NAbs after onabotulinumtoxinA treatment. At study exit, 16 of the 5876 subjects (0.3%) remained NAb positive. Due to the low incidence of NAb formation, no clear relationship was discernable between positive NAb results and gender, indication, dose level, dosing interval, treatment cycles, or the site of injection. Only five subjects who developed NAbs post-treatment were considered secondary nonresponders. Subjects who developed NAbs revealed no other evidence of immunological reactions or clinical disorders. This comprehensive meta-analysis confirms the low NAb formation rate following onabotulinumtoxinA treatment across multiple indications, and its limited clinical impact on treatment safety and efficacy. [ABSTRACT FROM AUTHOR]

Purpose: OnabotulinumtoxinA is an approved treatment for neurogenic detrusor overactivity in adults inadequately managed with anticholinergics, and more recently was approved in children on the basis of a phase 3, 48-week, single-treatment study (NCT01852045). Given the paucity of long-term pediatric data, we report on the continued safety in these patients after repeated onabotulinumtoxinA treatment. Materials and Methods: This was a multicenter, double-blind, repeat-treatment extension study (NCT01852058) in patients who entered from the preceding singletreatment study. Data were integrated across both studies. All patients (5-17 years) used clean intermittent catheterization and could receive dose escalations based on response to preceding treatment (50 U, 100 U, or 200 U onabotulinumtoxinA [not to exceed 6 U/kg]). Results: Overall, 95, 90, 55, and 11 patients received 1, 2, 3, and 4 treatments with onabotulinumtoxinA, respectively, and median (quartiles) duration of follow-up was 82 (65, 94) weeks. The safety profile was similar across doses and after repeat treatments. The most common treatment-emergent adverse event during cycles 1, 2, and 3 was urinary tract infection (31%, 34%, 22%). Three serious treatment-emergent adverse events related to study treatment (3/95; 3.2%) were reported during the study, which were all cases of urinary tract infection. Annualized urinary tract infection rates post-treatment were similar to pre-screening rates. There were no cases of autonomic dysreflexia, neutralizing antibodies, and treatment-emergent adverse events related to distant spread of toxin. Conclusions: OnabotulinumtoxinA continued to be well tolerated after repeated treatments in pediatric neurogenic detrusor overactivity patients with similar safety profiles across dose groups. Treatmentemergent adverse events were primarily urological with no new safety concerns. [ABSTRACT FROM AUTHOR]

Purpose: OnabotulinumtoxinA is approved in the Republic of Korea for the treatment of moderate-to-severe crow's feet lines (CFL) and glabellar lines (GL), separately or in combination. We assessed safety and effectiveness of onabotulinumtoxinA in real-world clinical practice. Patient and methods: This 4-year postmarketing surveillance study was conducted in the Republic of Korea in subjects with moderate-to-severe CFL. Subjects aged 18 to 75 years received onabotulinumtoxinA injections for CFL alone or in combination with GL. Safety assessments included adverse events (AEs), serious AEs (SAEs), and unexpected AEs (not noted in Korean prescribing information). Investigators assessed effectiveness via change from baseline in CFL. Results: The full analysis set comprised 695 subjects; 667 were in the safety set and 376 in the effectiveness set. In the safety set, mean ± SD age was 40.9±13.0 years; most subjects (87.3%) were female. More subjects were treated for CFL (69.9%) than CFL and GL simultaneously (30.1%). Eleven subjects experienced 14 AEs; 12 were mild in severity and 11 resolved without sequelae. Two cases of injection site pain in 2 subjects each were deemed possibly related to onabotulinumtoxinA. One unexpected SAE (acute renal failure) occurred in 1 subject (0.15%). All unexpected AEs (n=4) were mild and considered unrelated to treatment. Overall change from baseline showed CFL was improved in 375 subjects (99.7%) and unchanged in 1 subject (0.3%). Conclusion: OnabotulinumtoxinA was well tolerated and effective for treatment of CFL with or without GL in a real-world Korean population. No new safety concerns were identified. [ABSTRACT FROM AUTHOR]

It is important for patients that treatments for diabetes not increase cardiovascular (CV) risk. The objective of this analysis was to examine retrospectively the CV safety of exenatide BID, a GLP-1 receptor agonist approved for treating hyperglycemia in patients with type 2 diabetes not adequately controlled with diet and exercise. Individual participant data was pooled to assess the relative risk (RR) of CV events with exenatide BID versus a pooled comparator (PC) group treated with either placebo or insulin from 12 controlled, randomized, clinical trials ranging from 12-52 weeks. Mean baseline values for HbA1c (8.33-8.38%), BMI (31.3-31.5 kg/m²), and duration of diabetes (8 y) were similar between groups. Trials included patients with histories of microvascular and/or macrovascular disease. Customized primary major adverse CV events (MACE) included stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures. The Primary MACE RR (0.7; 95% CI 0.38, 1.31), calculated by the Mantel-Haenszel method (stratified by study), suggested that exenatide use (vs. PC) did not increase CV risk; this result was consistent across multiple analytic methods. Because the trials were not designed to assess CV outcomes, events were identified retrospectively from a list of preferred terms by physicians blinded to treatment. Other limitations included the low number of CV events, the short duration of trials (=1 y), and a single active comparator (insulin). The results of these analyses are consistent with those of a recent retrospective analysis of a large insurance database that found that patients treated with exenatide twice daily were less likely to have a CV event than were patients treated with other glucose-lowering therapies. [ABSTRACT FROM AUTHOR]

Two randomized, placebo-controlled studies evaluated the pulmonary function safety of onabotulinumtoxinA (onabotA) for treatment of upper and/or lower limb spasticity. Patients with stable baseline respiratory status received one or two treatments with placebo, 240 U, or 360 U of onabotA. Pulmonary function tests, adverse events, and efficacy were measured at least every 6 weeks for 18 weeks (Study 1) or 30 weeks (Study 2). Study 1 enrolled 109 patients (n = 36–37/group) and Study 2 enrolled 155 patients (n = 48–54/group). Mean baseline forced vital capacity (FVC) was 76–78% of predicted per group in Study 1 and 71% of predicted per group in Study 2. In Study 1, change from baseline FVC values were significantly (p < 0.05) decreased vs. placebo at weeks 3 (240 U −57 mL vs. placebo +110 mL) and 12 (360 U −6 mL vs. +167 mL placebo). In Study 2, change from baseline FVC values were significantly decreased in the 360 U group vs. placebo at weeks 6 (−78 mL vs. +49 mL placebo), 13 (−60 mL vs. +119 mL placebo), 18 (−128 mL vs. +80 mL placebo), and 24 (−82 mL vs. +149 mL placebo). Individual pulmonary function-related adverse events were not correlated with PFT decreases. The most frequent pulmonary-related adverse events were nasopharyngitis (Study 1) and upper respiratory tract infection (Study 2). Ashworth scores were significantly improved at multiple time points in both studies. Injection of onabotA for spasticity in patients with decreased pulmonary function, at single and repeated doses of up to 360 U, was associated with small but statistically significant decreases in FVC or forced expiratory volume 1 s (FEV1) (>12% and 200 mL) that were subclinical and not correlated with any adverse clinical pulmonary events. [ABSTRACT FROM AUTHOR]