Safety and Duration of Effect of 40U PrabotulinumtoxinA-xvfs for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients: A Phase II, Multi-Center, Randomized, Double Blind, Active-Controlled Trial.

BACKGROUND: Extending the duration of effect of botulinum toxins - by administering doses beyond those of the approved labels - has been an area of increasing interest in the field of aesthetics. OBJECTIVES: To investigate the safety and duration of effect of 40U prabotulinumtoxinA-xvfs (twice the approved dose and concentration) for the treatment of moderate-to-severe glabellar lines. METHODS: 154 adult patients were randomized 1:1:1 to a single treatment of either 40U prabotulinumtoxinA-xvfs (PRA 40, 5 injections of 8U/0.05 mL), or 20U of either prabotulinumtoxinA-xvfs (PRA 20) or onabotulinumtoxinA (ONA 20). Both 20U controls were administered as 5 injections of 4U/0.1 mL. Efficacy and safety were assessed on Days 2, 7 (by phone), 30 and every 30 days thereafter up to 365 days or until the patient had returned to Baseline. The primary effectiveness endpoint was the duration of effect (estimated by Kaplan-Meier analysis), defined as the number of days from Treatment Day (Baseline) to the day that glabellar line severity at maximum frown by investigator assessment returned to the baseline value. RESULTS: Patients had a mean age of 47 years (20-72 years); 69.5% had severe glabellar lines at Baseline. Of the 36 adverse events, 32 (88.9%) were mild and 4 (11.1%) were moderate in severity; none were serious. The median durations of effect were estimated to be 183, 149 and 148 days for PRA 40-, PRA 20- and ONA 20-treated patients, respectively. CONCLUSIONS: In this Phase II pilot study, 40U prabotulinumtoxinA-xvfs was observed to be safe and had a duration of 6 months.

PrabotulinumtoxinA for the treatment of glabellar lines in adults, 65 years of age and older: The fourth in a series of post hoc analyses of the phase III clinical study data.

BACKGROUND: Despite the absence of Phase III clinical trial data to support their use, 3.4% of all neurotoxin treatments performed internationally for esthetic purposes in 2020 were performed in patients 65 years of age and older. OBJECTIVES: To investigate the efficacy and safety of prabotulinumtoxinA for the treatment of moderate to severe glabellar lines in the subset of Phase III clinical trial participants who were 65 years of age and older. METHODS: Post hoc analyses were performed on all patients who had been treated with a single dose of 20 U prabotulinumtoxinA in the three 150-day, placebo-controlled Phase III glabellar line clinical studies. Patients were grouped by age: ≥65 years (n = 70) versus <65 years (n = 667). The endpoints of primary interest were the proportion of responders with a ≥1-point improvement from baseline at maximum frown on the 4-point Glabellar Line Scale and treatment-related adverse events. RESULTS: For the efficacy endpoint of primary interest, responder rates among patients 65 years of age and older were numerically less than those of patients less than 65 years by an absolute mean difference of just -2.7% across all visits; none of the differences at any visit were statistically significant. The most common treatment-related adverse event was headache, occurring in 5.7% of those 65 years of age and older and in 9.7% of those less than 65 years. CONCLUSIONS: 20 U prabotulinumtoxinA administered for the treatment of glabellar lines was efficacious in patients 65 years of age and older; it was also well tolerated by this cohort.

PrabotulinumtoxinA vs OnabotulinumtoxinA for the Treatment of Adult Males With Moderate to Severe Glabellar Lines: Post-hoc Analyses of the Phase III Clinical Study Data.

BACKGROUND: Despite a growing interest among men in cosmetic procedures such as botulinum toxin, comparator clinical trial data in this population are limited. OBJECTIVES: The authors sought to compare the efficacy and safety of prabotulinumtoxinA and onabotulinumtoxinA for the treatment of males with moderate to severe glabellar lines. METHODS: Post-hoc analyses were performed on the subpopulation of male patients treated with either a single dose of 20 U prabotulinumtoxinA (n = 25) or 20 U onabotulinumtoxinA (n = 31) in the EVB-003 Phase III glabellar line clinical study. One key efficacy endpoint was the proportion of responders with a ≥1-point improvement from baseline at maximum frown on the 4-point Glabellar Line Scale. RESULTS: Compared with onabotulinumtoxinA-treated males, the percentages of responders who had a ≥1-point improvement on the Glabellar Line Scale at maximum frown were higher at all postbaseline time points for prabotulinumtoxinA-treated males (P > 0.05 at all visits) by an absolute overall mean difference of 10.1% across all visits. Similar trends were observed for efficacy endpoints based on global aesthetic improvement and subject satisfaction. PrabotulinumtoxinA-treated males had a higher incidence of treatment-related headache and eyelid ptosis. CONCLUSIONS: The percentages of patients who met the definition of a responder were higher at almost all time points examined for prabotulinumtoxinA-treated males. Despite the high level of consistency across all measures, differences between the 2 treatment groups did not reach statistical significance. Further study is warranted to establish if these post-hoc analyses observations are reproducible in a larger male patient population.

PrabotulinumtoxinA for Treatment of Millennials With Moderate to Severe Glabellar Lines: Post Hoc Analyses of the Phase III Clinical Study Data.

BACKGROUND: The use of esthetic products by millennials is increasing, yet published clinical trial data in this population are limited. OBJECTIVE: To compare the efficacy and safety of prabotulinumtoxinA for the treatment of moderate to severe glabellar lines in millennial and nonmillennial patients. METHODS AND MATERIALS: Post hoc analyses were performed on the pooled population of all patients treated with 20U prabotulinumtoxinA in the 3 single-dose Phase III glabellar line clinical studies. Patients were grouped by age: millennials (born 1982-2000) versus nonmillennials (born ≤1981). One key efficacy end point was the proportion of responders with a ≥1-point improvement from baseline at maximum frown on the 4-point Glabellar Line Scale. Adverse events were also summarized. RESULTS: Responder rates among millennials (n = 65) were greater than those of nonmillennials (n = 668) by 7.7% on average across all visits; differences were statistically significant at Day 90. Responder rates at Day 90 were 90.2% and 76.1%, respectively (absolute difference of 14.0%, p = .01). Headache was the most common treatment-related adverse event, occurring in 9.0% and 9.4% of millennials and nonmillennials, respectively. CONCLUSION: A single dose of 20U prabotulinumtoxinA administered for the treatment of glabellar lines was similarly well-tolerated by both millennials and nonmillennials; overall, it was more efficacious in millennials.

The First of Two One-Year, Multicenter, Open-Label, Repeat-Dose, Phase II Safety Studies of PrabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients.

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin type A produced by Clostridium botulinum. OBJECTIVES: The authors sought to investigate the safety of prabotulinumtoxinA for treatment of glabellar lines. METHODS: This was a multicenter, open-label, repeat-dose, 1-year phase II safety study. Adults with moderate to severe glabellar lines at maximum frown, as assessed by the investigator on the validated 4-point photonumeric Glabellar Line Scale (0 = no lines, 1 = mild, 2 = moderate, 3 = severe), were enrolled. On day 0, patients received an initial treatment of 20 U prabotulinumtoxinA (4 U/0.1 mL freeze-dried formulation injected into 5 target glabellar sites). On and after day 90, patients received a repeat treatment (RT) if their Glabellar Line Scale score was ≥2 at maximum frown by investigator assessment. Safety was evaluated throughout the study. RESULTS: The 352 study patients received a median total dose of 60 U, that is, 3 treatments per year. Fifty-one patients (14.5%) experienced adverse events (AEs) assessed as possibly study drug related; 11.1% experienced study drug-related AEs after the initial treatment. With each RT, progressively lower percentages of patients experienced study drug-related AEs. Six patients (1.7%) experienced study drug-related AEs of special interest: 3 eyelid ptosis (0.9%), 2 speech disorder (0.6%), and 1 blepharospasm (0.3%). Seven patients (2.0%) experienced serious AEs; none were study drug related. Of the 2393 samples tested, 2 patients (0.6%) tested positive for antibotulinum toxin antibodies at a single postbaseline visit. CONCLUSIONS: The safety of RTs of 20 U of prabotulinumtoxinA for moderate to severe glabellar lines was first established in this early phase II study based on a broad range of outcomes.

The Second of Two One-Year, Multicenter, Open-Label, Repeat-Dose, Phase II Safety Studies of PrabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients.

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin type A produced by Clostridium botulinum. OBJECTIVES: The authors sought to investigate the safety of prabotulinumtoxinA for treatment of glabellar lines. METHODS: This was a multicenter, open-label, repeat-dose, 1-year phase II safety study. Adults with moderate to severe glabellar lines at maximum frown, as independently assessed by both investigator and patient on the validated 4-point photonumeric Glabellar Line Scale (0 = no lines, 1 = mild, 2 = moderate, 3 = severe), were enrolled. On day 0, patients received an initial treatment (IT) of 20 U prabotulinumtoxinA (4 U/0.1 mL final vacuum-dried formulation injected into 5 glabellar sites). On and after day 90, patients received a repeat treatment (RT) if their Glabellar Line Scale score was ≥2 at maximum frown by investigator assessment. Safety outcomes were evaluated throughout the study. RESULTS: The 570 study patients received a median total dose of 60 U, that is, 3 treatments. Sixty-one patients (10.7%) experienced adverse events (AEs) assessed as possibly study drug related; 6.5% experienced study drug-related AEs after the IT. With each RT, progressively lower percentages of patients experienced study drug-related AEs. Eight patients (1.4%) experienced study drug-related AEs of special interest: 5 experienced eyelid ptosis (0.9%), 3 eyebrow ptosis (0.5%), 1 blepharospasm (0.2%), and 1 blurred vision (0.2%). Seven patients (1.2%) experienced serious AEs, but none were study drug related. A total of 4060 serum samples were tested for antibotulinum toxin antibodies; no seroconversion was observed. CONCLUSIONS: The safety of RTs of 20 U of prabotulinumtoxinA for moderate to severe glabellar lines was confirmed in this second phase II study based on a broad range of outcomes.

PrabotulinumtoxinA for the Treatment of Moderate-to-Severe Glabellar Lines in Adult Patients With Skin of Color: Post Hoc Analyses of the US Phase III Clinical Study Data.

BACKGROUND: Limited US clinical data are available on the use of aesthetic products in patients with skin of color (SOC). OBJECTIVE: To compare the efficacy and safety of prabotulinumtoxinA for the treatment of glabellar lines in patients with and without SOC. METHODS AND MATERIALS: Post hoc analyses were performed on the pooled population of all 492 patients treated with 20U prabotulinumtoxinA in the 2 US single-dose Phase III glabellar line clinical studies. Patients were grouped by Fitzpatrick skin Type: IV + V + VI (with SOC) versus I + II + III (without SOC). The primary efficacy end point was the proportion of responders with a ≥1-point improvement from baseline at maximum frown on the 4-point Glabellar Line Scale. Adverse events (AEs) were also summarized. RESULTS: Responder rates among patients with SOC (n = 140) were lower than those without SOC (n = 352), by 5.9% on average across all visits; at no time point were differences statistically significant. At Day 30, responder rates were 94.0% and 96.0%, respectively (p = .401). Headache was the most common treatment-related AE, occurring in 12.1% and 8.2% of patients with and without SOC, respectively. CONCLUSION: A single dose of 20U prabotulinumtoxinA was well tolerated and similar in effectiveness in patients with and without SOC for the treatment of glabellar lines.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Phase III, Non-Inferiority Study Comparing PrabotulinumtoxinA and OnabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients.

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin type A produced by Clostridium botulinum. OBJECTIVES: The authors sought to investigate the efficacy and safety of prabotulinumtoxinA compared to onabotulinumtoxinA and placebo for the treatment of glabellar lines. METHODS: This was a 150-day, multicenter, double-blind, controlled, single-dose Phase III study. Adult patients (n = 540) with moderate to severe glabellar lines at maximum frown as assessed by the investigator on the validated 4-point Glabellar Line Scale (0 = no lines, 1 = mild, 2 = moderate, 3 = severe), who also felt that their glabellar lines had an important psychological impact, were enrolled. Patients were randomized 5:5:1 to receive a single treatment (0.1 mL injected into each of 5 glabellar sites) of 20 U prabotulinumtoxinA (n = 245), 20 U onabotulinumtoxinA (n = 246), or placebo (n = 49). The primary efficacy endpoint was the proportion of responders (patients with a Glabellar Line Scale score of 0 or 1 at maximum frown by investigator assessment) on day 30. RESULTS: Responder rates for the primary efficacy endpoint were 87.2%, 82.8%, and 4.2% in the prabotulinumtoxinA, onabotulinumtoxinA, and placebo groups, respectively. The absolute difference between prabotulinumtoxinA and onabotulinumtoxinA groups was 4.4% (95% confidence interval [-1.9, 10.8]). Given that the lower bound of the 95% confidence interval for the difference was less than -10.0%, noninferiority of prabotulinumtoxinA vs onabotulinumtoxinA was concluded. Five patients (3 prabotulinumtoxinA, 1.2%; 1 onabotulinumtoxinA, 0.4%; 1 placebo, 2.0%) experienced serious adverse events, none of which were study drug related. CONCLUSIONS: A single treatment of 20 U prabotulinumtoxinA was safe and effective and noninferior to 20 U onabotulinumtoxinA for the treatment of moderate to severe glabellar lines.

Efficacy and Safety of PrabotulinumtoxinA for the Treatment of Glabellar Lines in Adult Subjects: Results From 2 Identical Phase III Studies.

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin Type A produced by Clostridium botulinum. OBJECTIVE: To investigate the efficacy and safety of prabotulinumtoxinA for the treatment of glabellar lines. MATERIALS AND METHODS: Adult subjects (n = 330 in EV-001; n = 324 in EV-002) with moderate to severe glabellar lines at maximum frown on the 4-point Glabellar Line Scale (GLS; 0 = no lines, 1 = mild, 2 = moderate, and 3 = severe) were enrolled in 1 of 2 identical 150-day, double-blind, placebo-controlled, single-dose, Phase III studies. Subjects were randomized 3:1 to receive 20-U prabotulinumtoxinA or placebo. The primary efficacy end point was the proportion of responders on Day 30 where the investigator and subject independently agreed that a ≥2-point improvement had occurred on the GLS at maximum frown from Day 0. Adverse events (AEs) were evaluated throughout the study. RESULTS: Responder rates in the prabotulinumtoxinA and placebo groups were 67.5% and 1.2% in EV-001 and 70.4% and 1.3% in EV-002; absolute differences between groups were 66.3% and 69.1% in EV-001 and EV-002, respectively (both p < .001). No serious AE in either study was assessed as study drug related. CONCLUSION: In these studies, a single dose of 20-U prabotulinumtoxinA was safe and effective for the treatment of glabellar lines.

Anti-infective external coating of central venous catheters: a randomized, noninferiority trial comparing 5-fluorouracil with chlorhexidine/silver sulfadiazine in preventing catheter colonization.

OBJECTIVE: The antimetabolite drug, 5-fluorouracil, inhibits microbial growth. Coating of central venous catheters with 5-fluorouracil may reduce the risk of catheter infection. Our objective was to compare the safety and efficacy of central venous catheters externally coated with 5-fluorouracil with those coated with chlorhexidine and silver sulfadiazine. DESIGN: Prospective, single-blind, randomized, active-controlled, multicentered, noninferiority trial. SETTING: Twenty-five US medical center intensive care units. PATIENTS: A total of 960 adult patients requiring central venous catheterization for up to 28 days. INTERVENTIONS: Patients were randomized to receive a central venous catheter externally coated with either 5-fluorouracil (n = 480) or chlorhexidine and silver sulfadiazine (n = 480). MEASUREMENTS AND MAIN RESULTS: The primary antimicrobial outcome was a dichotomous measure (<15 colony-forming units or ≥ 15 colony-forming units) for catheter colonization determined by the roll plate method. Secondary antimicrobial outcomes included local site infection and catheter-related bloodstream infection. Central venous catheters coated with 5-fluorouracil were noninferior to chlorhexidine and silver sulfadiazine coated central venous catheters with respect to the incidence of catheter colonization (2.9% vs. 5.3%, respectively). Local site infection occurred in 1.4% of the 5-fluorouracil group and 0.9% of the chlorhexidine and silver sulfadiazine group. No episode of catheter-related bloodstream infection occurred in the 5-fluorouracil group, whereas two episodes were noted in the chlorhexidine and silver sulfadiazine group. Only Gram-positive organisms were cultured from 5-fluorouracil catheters, whereas Gram-positive bacteria, Gram-negative bacteria, and Candida were cultured from the chlorhexidine and silver sulfadiazine central venous catheters. Adverse events were comparable between the two central venous catheter coatings. CONCLUSIONS: Our results suggest that central venous catheters externally coated with 5-fluorouracil are a safe and effective alternative to catheters externally coated with chlorhexidine and silver sulfadiazine when used in critically ill patients.

A lung biopsy tract plug for reduction of postbiopsy pneumothorax and other complications: results of a prospective, multicenter, randomized, controlled clinical study.

PURPOSE: To evaluate the ability of an expanding hydrogel lung biopsy tract plug ("plug") to reduce rates of pneumothoraces and other complications associated with computed tomography (CT)-guided lung biopsy. MATERIALS AND METHODS: A total of 339 subjects (mean age, 67 years) who underwent lung biopsy of indeterminate masses, without immediate postsample CT evidence of a pneumothorax, were randomized at 15 U.S. centers. Treatment subjects (n = 170) received a plug deployed through the coaxial needle just before the needle was removed. Control subjects (n = 169) did not receive a plug. The primary end point was defined as the absence of pneumothorax on chest radiographs at all three required postprocedure assessments (30- to 60-minute, 24-hour, 30-day); analysis was stratified by any smoking history and study site. A central laboratory performed blinded independent interpretation of the radiographs. RESULTS: Among the 287 subjects who completed all postprocedure assessments, significantly more treatment subjects than control subjects achieved the primary end point (127 of 150, 85% vs 95 of 137, 69%; P = .002). Among all 339 randomized subjects, the odds of achieving the primary end point were 4.4 times greater for nonsmokers than they were for smokers (95% confidence interval, 1.7, 11.0; P = 0.002); study site had no statistically significant effect. Compared with control subjects, treatment subjects had fewer pneumothoraces (30 of 170, 18% vs 53 of 169, 31%), fewer chest tubes placed (6 of 170, 4% vs 18 of 169, 11%), and fewer postbiopsy hospital admissions (16 of 170, 9% vs 23 of 169, 14%). CONCLUSIONS: The lung biopsy tract plug significantly reduced rates of pneumothorax in patients undergoing CT-guided lung biopsy. Rates of chest tube placement and postprocedure hospital admission were also reduced.

The safety and effectiveness of the retrievable option inferior vena cava filter: a United States prospective multicenter clinical study.

PURPOSE: To evaluate the safety and effectiveness of the retrievable Option inferior vena cava (IVC) filter in patients at risk for pulmonary embolism (PE). MATERIALS AND METHODS: This was a prospective, multicenter, single-arm clinical trial. Subjects (N = 100) underwent implantation of the IVC filter and were followed for 180 days; subjects whose filters were later removed were followed for 30 days thereafter. The primary objective was to determine whether the one-sided lower limit of the 95% CI for the observed clinical success rate was at least 80%. Clinical success was defined as technical success (deployment of the filter such that it was judged suitable for mechanical protection from PE) without subsequent PE, significant filter migration or embolization, symptomatic caval thrombosis, or other complications. RESULTS: Technical success was achieved in 100% of subjects. There were eight cases of recurrent PE, two cases of filter migration (23 mm), and three cases of symptomatic caval occlusion/thrombosis (one in a subject who also experienced filter migration). No filter embolization or fracture occurred. Clinical success was achieved in 88% of subjects; the one-sided lower limit of the 95% CI was 81%. Retrieval was successful at a mean of 67.1 days after implantation (range, 1-175 d) for 36 of 39 subjects (92.3%). All deaths (n = 17) and deep vein thromboses (n = 18) were judged to have resulted from preexisting or intercurrent illnesses or interventions and unrelated to the filter device; all deaths were judged to be unrelated to PE. CONCLUSIONS: Placement and retrieval of the Option IVC filter were performed safely and with high rates of clinical success.

Inhibition of neointimal hyperplasia in a sheep model of dialysis access failure with the bioabsorbable Vascular Wrap paclitaxel-eluting mesh.

OBJECTIVE: This study evaluated the effect of a bioabsorbable mesh containing paclitaxel on neointimal hyperplasia in a sheep model of dialysis access failure. METHODS: Forty neutered male sheep were randomized to one of five parallel groups: no mesh; or a 3-cm x 6-cm mesh with 0.0, 0.3, 0.7, or 1.2 microg/mm(2) of paclitaxel for a total dose of 0.0, 0.6, 1.3, or 2.2 mg, respectively. Commercially available 6-mm internal diameter expanded polytetrafluoroethylene grafts were surgically placed between the left common carotid artery and the right external jugular vein. For those animals randomized to one of the mesh groups, the mesh was placed around the distal end of the graft and venous anastomosis. Patency was assessed at weekly intervals throughout the study. Animals were euthanized 8 weeks after implantation, and grafts and veins were harvested. After histologic processing, six cross sections were cut at the venous end of the graft and vessel. The primary and secondary efficacy outcome measures, respectively, were the area and capillary density of the neointima at the graft-vein anastomosis. Histologic analyses were also performed to investigate the effects of the paclitaxel-eluting mesh on the anastomotic site. RESULTS: Grafts occluded before the scheduled sacrifice in five animals, and they were excluded from the study and not replaced. Control animals developed significant neointimal hyperplasia at the cross section taken perpendicular to the graft at its most distal end: the neointimal area measured 10.5 +/- 6.8 mm(2) in the no mesh group and 6.4 +/- 3.2 mm(2) in the zero-dose mesh group (P = .28). In contrast, neointimal area was significantly reduced in the paclitaxel mesh groups: 0.9 +/- 1.4 mm(2) in the 0.3 microg/mm(2) group (P = .008 vs zero-dose mesh), 1.3 +/- 1.5 mm(2) in the 0.7 microg/mm(2) group (P = .004 vs zero-dose mesh), and 1.2 +/- 1.4 mm(2) in the 1.2 microg/mm(2) group (P = .008 vs zero-dose mesh). Capillary density in the neointima at the graft-vein anastomosis decreased with paclitaxel and was significantly reduced in the paclitaxel mesh groups with 0.3 and 1.2 mug/mm(2) compared with the zero-dose mesh control (3.6 +/- 2.9 vs 8.9 +/- 5.6 per mm(2) [P = .022] and 1.1 +/- 1.7 vs 8.9 +/- 5.6 per mm(2) [P = .001] respectively). The paclitaxel mesh had no significant effect on healing of the anastomosis or on the thickness of the adjacent vein. CONCLUSIONS: In this model, the paclitaxel-eluting mesh significantly reduced neointimal hyperplasia and neointimal capillary density without apparent toxicity to the adjacent vein.