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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]

Background: Although gender medicine has been promoted in medical research and patient care, limited information is available on sex-specific differences in response to first-line Helicobacter pylori eradication therapy. Therefore, this retrospective study investigated sex-specific differences in response to first-line H. pylori eradication therapy with vonoprazan, amoxicillin, and clarithromycin. Method: The study included 314 patients who received vonoprazan-based triple therapy (20 mg vonoprazan, 750 mg amoxicillin, and 200 or 400 mg clarithromycin; twice daily for 7 days) as first-line H. pylori eradication therapy at Fuyoukai Murakami Hospital from March 1, 2015, to April 30, 2019. First-line eradication rates were determined by intention-to-treat (ITT) and per protocol (PP) analyses. Sex-specific differences in the rate of drug-related treatment-emergent adverse events (TEAEs) were also monitored. Fisher’s exact test was used for identifying sex-specific differences. Results: First-line eradication rates were 95% in ITT and PP analyses regardless of sex, without significant sex-specific differences [ITT analyses: males 95.3% (203/213) vs. females 96.0% (97/101), p = 1.0; PP analyses: males 95.3% (203/213) vs. females 96.0% (95/99), p = 1.0]. However, the rate of drug-related TEAEs was significantly higher in females than in males [males 4.2% (9/213) vs. females 17.8% (18/101), p 0.001]. In particular, skin rash occurred only in females [males 0% (0/213) vs. females 10.9% (11/101), p 0.00001]. Conclusion: Females experienced more drug-related TEAEs than males during first-line H. pylori eradication therapy with vonoprazan-based triple therapy. In particular, skin rash was observed only in females.

To evaluate long-term efficacy and safety of extended treatment with adalimumab in patients with noninfectious intermediate, posterior, or panuveitis. Open-label, multicenter, phase 3 extension study (VISUAL III). Adults who had completed a randomized, placebo-controlled phase 3 parent trial (VISUAL I or II) without treatment failure (inactive uveitis) or who discontinued the study after meeting treatment failure criteria (active uveitis). Patients received subcutaneous adalimumab 40 mg every other week. Data were collected for ≤ 362 weeks. Adverse events (AEs) were recorded until 70 days after the last dose. Long-term safety and quiescence; other efficacy variables included inflammatory lesions, anterior chamber cell and vitreous haze grade, macular edema, visual acuity, and dose of uveitis-related systemic corticosteroids. At study entry, 67% of patients (283/424) showed active uveitis and 33% (141/424) showed inactive uveitis; 60 patients subsequently met exclusion criteria, and 364 were included in the intention-to-treat analysis. Efficacy variables were analyzed through week 150, when approximately 50% of patients (214/424) remained in the study. Patients showing quiescence increased from 34% (122/364) at week 0 to 85% (153/180) at week 150. Corticosteroid-free quiescence was achieved by 54% (66/123) and 89% (51/57) of patients with active or inactive uveitis at study entry. Mean daily dose of systemic corticosteroids was reduced from 9.4 ± 17.1 mg/day at week 0 (n = 359) to 1.5 ± 3.9 mg/day at week 150 (n = 181). The percentage of patients who achieved other efficacy variables increased over time for those with active uveitis at study entry and was maintained for those with inactive uveitis. The most frequently reported treatment-emergent AEs of special interest were infections (n = 275; 79 events/100 patient-years [PY]); AEs and serious AEs occurred at a rate of 396 events/100 PY and 15 events/100 PY, respectively. Long-term treatment with adalimumab led to quiescence and reduced corticosteroid use for patients who entered VISUAL III with active uveitis and led to maintenance of quiescence for those with inactive uveitis. AEs were comparable with those reported in the parent trials and consistent with the known safety profile of adalimumab. [ABSTRACT FROM AUTHOR]

Objective: We explore factors that may have contributed to differences in treatment‐emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials. Background: Phase 2 and phase 3 trials showed that the centrally penetrant 5‐HT1F agonist, lasmiditan, was effective; higher frequency and severity of adverse events (AEs) were seen in phase 2. Methods: This work represents a hybrid of a review of primary documents and study reports with additional post hoc analyses. Protocols, informed consents, data collection forms, and methodologies were reviewed. This information was supplemented by results from the clinical study reports and post hoc analyses of individual patient data from each trial. Results: For lasmiditan 100 and 200 mg, in phase 2, the incidence of ≥1 AE was 72‐86% (26% severe), while in phase 3 was 36‐43% (2% severe). The most common AEs in all studies were CNS‐related. The phase 2 consent form was more descriptive of AEs than phase 3. In phase 2, patients recorded AEs and severity in a paper diary that warned about drowsiness and dizziness. In phase 3, patients recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan that they had not felt with a migraine before, and were contacted to determine if an AE had occurred. In phase 2, the AE Schwindel was variably translated from German as "vertigo" or "dizziness," while phase 3 vertigo cases were queried to ensure there was a sensation of rotation or movement. History of recurrent dizziness and/or vertigo was exclusionary in phase 3. Conclusions: This work illustrates how informed consent wording, AE collection methods, translation, exclusion criteria, and other factors may be important determinants for reporting of the frequency and severity of AEs in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Although gender medicine has been promoted in medical research and patient care, limited information is available on sex-specific differences in response to first-line Helicobacter pylori eradication therapy. Therefore, this retrospective study investigated sex-specific differences in response to first-line H. pylori eradication therapy with vonoprazan, amoxicillin, and clarithromycin. Method: The study included 314 patients who received vonoprazan-based triple therapy (20 mg vonoprazan, 750 mg amoxicillin, and 200 or 400 mg clarithromycin; twice daily for 7 days) as first-line H. pylori eradication therapy at Fuyoukai Murakami Hospital from March 1, 2015, to April 30, 2019. First-line eradication rates were determined by intention-to-treat (ITT) and per protocol (PP) analyses. Sex-specific differences in the rate of drug-related treatment-emergent adverse events (TEAEs) were also monitored. Fisher s exact test was used for identifying sex-specific differences. Results: First-line eradication rates were >95% in ITT and PP analyses regardless of sex, without significant sex-specific differences [ITT analyses: males 95.3% (203/213) vs. females 96.0% (97/101), p = 1.0; PP analyses: males 95.3% (203/213) vs. females 96.0% (95/99), p = 1.0]. However, the rate of drug-related TEAEs was significantly higher in females than in males [males 4.2% (9/213) vs. females 17.8% (18/101), p < 0.001 J. In particular, skin rash occurred only in females [males 0% (0/213) vs. females 10.9% (11/101), p < 0.00001]. Conclusion: Females experienced more drug-related TEAEs than males during first-line H. pylori eradication therapy with vonoprazan-based triple therapy. In particular, skin rash was observed only in females. [ABSTRACT FROM AUTHOR]

Relative risks of treatment-emergent adverse events (TEAEs) and related hospitalization is most accurate when accounting for treatment exposure. AZA-AML-001 showed azacitidine (AZA) prolonged overall survival versus conventional care regimens (CCR) in older patients (≥65 years) with acute myeloid leukemia (AML) by 3.9 months. Preselection of CCR before study randomization allows evaluation of AZA safety in patient subgroups with similar clinical features. Within preselection groups, AZA exposure was greater than each CCR. Incidence rates (IRs; numbers of events normalized for drug exposure time) of hospitalizations and days in hospital for TEAEs per patient-year of exposure were to varying degrees lower with AZA versus each CCR. Overall survival was significantly prolonged with AZA versus best supportive care (BSC) in AZA-AML-001; this analysis showed 55% and 41% reductions in IRs of TEAE-related hospitalization and days in hospital, respectively, with AZA versus BSC. Older patients with AML unable to tolerate intensive therapy should be offered active low-intensity treatment. [ABSTRACT FROM PUBLISHER]

Background: The widespread use of artesunate-amodiaquine (ASAQ) for treating uncomplicated malaria makes it important to gather and analyse information on its tolerability. Methods: An individual-patient tolerability analysis was conducted using data from eight randomized controlled clinical trials conducted at 17 sites in nine sub-Saharan countries comparing ASAQ to other anti-malarial treatments. All patients who received at least one dose of the study drug were included in the analysis. Differences in adverse event (AE) and treatment emergent adverse event (TEAE) were analysed by Day 28. Results: Of the 6,179 patients enrolled (74% <5 years of age), 50% (n = 3,113) received ASAQ, 20% (n = 1,217) another ACT, and 30% (n = 1,849) a non-ACT (combination or single-agent) treatment. Overall, 8,542 AEs were recorded. The proportion of patients experiencing at least one gastro-intestinal AE on ASAQ was 43% (and higher than that with artemether-lumefantrine and dihydroartemisinin-piperaquine at two sites), and was 23% for any other AEs (not different from other treatments). Specifically, the risk of diarrhoea, vomiting, cough and weakness was lower with artemether-lumefantrine; artemether-lumefantrine and dihydroartemisinin-piperaquine carried a higher risk of pruritus, chloroquine-SP had a higher risk of nausea. Parasitological recurrence increased the risk of occurrence of any AE. No other difference was detected. Comparing AE to TEAE in patients who had pre-treatment occurrence and grades of intensity recorded, AEs were significantly more related to the pre-treatment prevalence of the symptom (p = 0.001, Fisher test); AEs overestimated TEAEs by a factor ranging from none to five-fold. The overall incidence of serious AEs (SAEs) with ASAQ was nine per 1,000 (29/3,113) and mortality was one per 1,000 (three deaths, none drug-related); both were similar to other treatments. Conclusion: ASAQ was comparatively well-tolerated. Safety information is important, and must be collected and analysed in a standardized way. TEAEs are a more objective measure of treatment-induced toxicity. [ABSTRACT FROM AUTHOR]

Background: Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib., Objective: We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options., Methods: This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0., Results: A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC (P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events., Limitations: Abbreviated follow-up time because of study termination upon FDA approval was a limitation., Conclusion: This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: According to meta-analyses and reviews, subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are beneficial in patients with allergic rhinitis (AR) and allergic asthma (AA) induced by house dust mites (HDMs). However, the reported effect sizes have varied greatly from one study to another., Objective: We sought to perform an evidence-based medicine assessment of commercially available SCIT and SLIT formulations in patients with HDM-induced AA and HDM-induced AR., Methods: We searched for double-blind, placebo-controlled randomized clinical trials and analyzed study designs, doses, regimens, patient-reported outcomes, safety reporting, and compliance., Results: Forty-four studies met our inclusion criteria. Some studies tested both SLIT and SCIT or scored both AA and AR outcomes; therefore we reviewed 35 treatment arms in patients with AA (20 for SCIT and 15 for SLIT) and 23 treatment arms in patients with AR (7 for SCIT and 16 for SLIT). The treatment duration ranged from 6 weeks to 3 years. For SCIT, the dose of Der p 1 major allergen (when reported) ranged from 7 to 30 μg for maintenance doses and 60 to 420 μg for cumulative doses. For SLIT, the doses of Der p 1 (when reported) were 0.8 to 70 μg for maintenance doses and 60 to 23,695 μg for cumulative doses. Safety data were often absent or poorly reported. A statistically significant active versus placebo symptom score was observed more frequently for SCIT than for SLIT., Conclusion: There is no consensus on basic treatment parameters (eg, dose and duration) in HDM SCIT and SLIT. There is an urgent need for rigorous, long-term, double-blind, placebo-controlled randomized clinical trials with an efficacy criterion that reflects the particular features of HDM-induced allergic disease., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: H1-receptor inverse agonists are used effectively for treating several symptoms of allergic rhinitis, including nasal itching, rhinorrhea, and sneezing, although most agents are not very effective in treating nasal congestion., Objective: This study evaluated the relative efficacy of a novel selective H3-receptor antagonist, JNJ-39220675, in preventing nasal congestion induced by exposing participants with ragweed allergy to ragweed allergen in an environmental exposure chamber model., Methods: In this single-dose, patient-blind, double-dummy, placebo- and active-controlled, phase IIa cross-over study, 53 participants were randomized to JNJ-39220675 plus placebo, placebo plus pseudoephedrine, or only placebo. The primary efficacy assessment was change in nasal patency assessed by measuring the minimal cross-sectional area of the nasal cavity by using acoustic rhinometry. Secondary assessment included total nasal symptom scores (TNSSs) over the 8-hour environmental exposure chamber exposure period., Results: Smaller decreases in minimal cross-sectional area were observed after JNJ-39220675 (least square mean difference, -0.126; P = .06) and pseudoephedrine (least square mean difference, -0.195; P = .004) treatment compared with placebo. The means for the baseline-adjusted area under the curve of TNSSs were significantly smaller for JNJ-39220675 (P = .0003) and pseudoephedrine (P = .04) versus placebo. JNJ-39220675 was significantly effective in treating all 4 individual symptoms (P ≤ .05 for all scores) compared with placebo, whereas pseudoephedrine only showed a trend for improvement in individual symptom scores of the TNSS. Insomnia was the most frequent adverse event (17.3%) associated with JNJ-39220675 treatment., Conclusion: Prophylactic treatment with the H3-antagonist JNJ-39220675 relieved allergen-induced nasal congestion by using standard nasal symptom scoring; however, in contrast to pseudoephedrine, it only showed a trend for increasing nasal patency by using objective measures., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Onychomycosis is effectively treated with terbinafine and itraconazole. However, frequent repeated dosing is required, and hepatic and cardiac adverse events may occur., Objectives: Evaluate efficacy and safety of albaconazole, a novel triazole, for once-weekly treatment of distal subungual onychomycosis of the great toenail., Methods: This double-blind, phase II study randomized 584 patients to receive albaconazole 100 to 400 mg or placebo weekly for 24 or 36 weeks. Effective treatment was measured as mycologic cure and clear or almost clear nail at week 52., Results: All treatment groups achieved greater effective treatment rates (21%-54%) compared to placebo (1%; P < .001 for all groups) at week 52. Effective treatment was attained at week 24 in ≥5% of patients in most groups. Most adverse events were mild or moderate, and treatment-related adverse events were all ≤3%. No treatment-related hepatic or cardiac serious adverse events were observed., Limitations: The follow-up period was likely too short to detect maximal efficacy; cure rates were increasing at study end. The efficacy and tolerability of albaconazole were not compared with other available treatments, and the global change in target toenail scale was subjective., Conclusions: Albaconazole was well tolerated at all doses and resulted in high cure rates for onychomycosis., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)