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Donidalorsen, a prekallikrein-directed antisense oligonucleotide indicated for prophylaxis of hereditary angioedema (HAE) attacks in patients aged ≥12 years, demonstrated efficacy and acceptable safety in the phase 3, placebo-controlled OASIS-HAE trial (NCT05139810). Here, we report 1-year results from the corresponding open-label extension (OLE) cohort of the OASISplus study (NCT05392114). OASISplus included patients who rolled over from OASIS-HAE. Patients who received donidalorsen 80 mg or placebo subcutaneously every 4 weeks (Q4W) in OASIS-HAE received donidalorsen Q4W in OASISplus. Patients who received donidalorsen 80 mg or placebo every 8 weeks (Q8W) in OASIS-HAE received donidalorsen Q8W or Q4W, if not attack-free in the final 8 weeks of OASIS-HAE. The primary endpoint was safety (ie, incidence of treatment-emergent adverse events [TEAEs]). Secondary endpoints included the monthly rate of HAE attacks and Angioedema Quality of Life (AE-QoL). The OLE cohort included 83 patients (Q4W, n=69 [83%]; Q8W, n=14 [17%]). Of these, 75 (90.4%) completed Year 1, and 6 patients receiving donidalorsen Q8W in OASIS-HAE switched to the Q4W dosing group in the OLE. Median donidalorsen exposure was 392.3 days. From Weeks 0 to 52, reductions in mean HAE attack rate from OASIS-HAE baseline were 94% (Q4W) and 95% (Q8W), and patients reported clinically meaningful improvements in mean AE-QoL total score at Week 52 (Q4W, 28.1 points; Q8W, 26.7 points). Twenty-two (27%) patients reported treatment-related TEAEs; none were serious, and injection-site reactions were the most frequently reported. Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment.

An innovative method of operating 3-phase, 4-wire voltage–source converters, based on decoupled P–Q control of individual phases, is presented. Individual-phase control has six independent degrees of control freedom to deal with both symmetrical and asymmetrical operating conditions. Experimental tests on a laboratory distribution static synchronous compensator (D-STATCOM) show that individual-phase control can simultaneously (i) support the voltages of unbalanced 3-phase loads against droop; (ii) equalise the complex powers at source-side of the transmission line; (iii) balance the voltage magnitudes and (iv) balance the angles of ‘ac’ voltages at the point-of-common-coupling.

Clinical trials for Alzheimer's disease (AD) must be registered on clinicaltrials.gov. The registry presents a variety of types of information related to the planned clinical trial. We assess clinicaltrials.gov to document and compare aspects of drug development across the AD pipeline. Currently, there are 138 drugs being assessed in 182 clinical trials in the AD pipeline. Biological disease‐targeted therapies (DTTs) comprise 30% of the pipeline; small molecule DTTs account for 43% of the pipeline; drugs addressing cognitive enhancement account for 14% of the pipeline; and drugs aiming to ameliorate neuropsychiatric symptoms in participants with AD contribute 11% of the pipeline. Biomarkers are among the primary outcomes of 27% of active trials. Repurposed agents represent 33% of the pipeline agents. The pipeline has more trials and more drugs compared to the 2024 pipeline. Highlights The 2025 Alzheimer's disease drug development pipeline hosts 182 trials and 138 novel drugs. The 2025 Alzheimer's disease drug development pipeline is diverse, with agents that address 15 basic disease processes. The 2025 Alzheimer's disease drug development pipeline has more trials and more drugs than the 2024 pipeline. Biomarkers play an important role in current trials to determine trial eligibility and as outcomes of trials. Repurposed agents comprise approximately one‐third of the agents and trials in the 2025 Alzheimer's disease drug development pipeline.

From voltage and current signals it is possible to obtain relevant information for solving some problems in several industrial and scientific applications as power quality (PQ) monitoring, monitoring and diagnosis of electrical machines, electric systems protection and control. At present, the PQ monitoring, measure through a set of PQ indices (PQI), is an important topic for the industrial sector since a poor PQ, characterised by the presence of harmonics in the power line, produces irregular or wrong operation of protection systems, excessive neutral currents in 3-phase four-wire systems, overheating of motors, transformers, capacitor banks and wiring in general. The PQI calculation is performed by many techniques proposed in the literature; however, they do not have either good performance for transient signals or the requirements for satisfying the power standards. This work proposes the assessment of the PQI-based in neural networks for transient or stationary signals in 3-phase power systems without losing the power standard requirements. Besides, this work contributes to the industrial application field by allowing the continuous and online monitoring of the PQI thanks to the field programmable gate array implementation of the proposed methodology.

PurposeThis trial was conducted to confirm the non-inferiority of remimazolam versus propofol in the induction and maintenance of general anesthesia in surgical patients.MethodsSurgical patients (n = 375) were randomized to remimazolam started at 6 or 12 mg/kg/h by continuous intravenous (IV) infusion until the loss of consciousness (LoC), followed by 1 mg/kg/h to be adjusted as appropriate until the end of surgery or IV propofol administered as a slow bolus of 2.0–2.5 mg/kg until LoC followed by 4–10 mg/kg/h until the end of surgery. Efficacy was measured via the combined primary endpoint of no intraoperative awakening/recall, no need for rescue sedatives, and no body movements. Adverse events and adverse drug reactions (ADRs) were monitored for safety.ResultsEfficacy rates were 100% in all treatment groups, and the non-inferiority of remimazolam was demonstrated [95% confidence interval (− 0.0487; 0.0250)]. The time to LoC was longer in the remimazolam 6 (p < 0.0001) and 12 mg/kg/h (p = 0.0149) groups versus propofol. The time to extubation was longer in both remimazolam groups versus the propofol group (p ≤ 0.0001). The incidence of ADRs was similar in the remimazolam groups (39.3% and 42.7%, respectively) compared with the propofol group (61.3%). Decreased blood pressure occurred in 20.0% and 24.0% of patients treated with 6 and 12 mg/kg/h remimazolam, respectively, compared with 49.3% of patients receiving propofol. Injection site pain was reported in 18.7% of propofol patients but not in those receiving remimazolam.ConclusionsThis trial demonstrated that remimazolam was well tolerated and non-inferior to propofol with regard to efficacy as a sedative hypnotics for general anesthesia.Clinical trial registrationThis trial is registered with the Japan Pharmaceutical Information Center - Clinical Trials Information (JapicCTI). JapicCTI number: 121973

Benvitimod (tapinarof), an aryl hydrocarbon receptor (AhR) agonist approved for treating plaque psoriasis, is being investigated as a potential treatment for atopic dermatitis (AD). The aim of this study was to evaluate the efficacy and safety of benvitimod 1% cream in patients aged 2 years or older with AD. This randomized controlled trial enrolled 271 Chinese patients with AD aged ≥2 years, who received either benvitimod 1% cream (n = 183) or vehicle cream (n = 88) twice daily for 8 weeks in a 2:1 ratio at 35 sites in China from June to November 2023. The primary endpoint was the proportion of patients achieving a 75% improvement in the Eczema Area and Severity Index (EASI) 75 at week 8. Secondary endpoints included achievement of Investigator's Global Assessment (IGA) scores of 0/1, 90% EASI improvement (EASI 90), and ≥3-point reduction in Peak Pruritus Numerical Rating Scale (PP-NRS). Treatment-emergent adverse events (TEAEs) were monitored for safety evaluation. Furthermore, a subset of patients (n = 43) opted into a 44-week open-label extension. At week 8, a significantly higher proportion of patients treated with benvitimod achieved EASI 75 compared to those receiving vehicle (54.4% [n = 183] vs. 25.5% [n = 88]; P <0.001). The benvitimod group also showed superior results across all secondary endpoints: IGA 0/1 (46.2% [n = 183] vs. 21.4% [n = 88]; P <0.001), EASI 90 (33.9% [58/171] vs. 13.5% [10/74]; P <0.001), and ≥3-point decrease in PP-NRS (54.0% [47/87] vs. 27.9% [12/43]; P <0.01). TEAEs occurred in 51.4% (94/183) of benvitimod-treated patients vs. 43.2% (38/88) of vehicle-treated patients, with most events being mild to moderate in severity. Benvitimod 1% cream demonstrated favorable efficacy and safety in adult and pediatric patients with AD, supporting its potential as a novel topical treatment option. chinadrugtrials.org.cn, CTR20231413.

Background Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting. Methods In this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m 2 ) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review. Results Between Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment. Conclusions The primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer. Trial registration ClinicalTrials.gov, NCT03588091

Drug developers sometimes launch phase 3 (P3) trials without supporting evidence from phase 2 (P2) trials. We call this practice “P2 bypass.” The aims of this study were to estimate the prevalence of P2 bypass and to compare the safety and efficacy results for P3 trials that bypassed with those that did not. We created a sample of P3 solid tumor trials registered on ClinicalTrials.gov with primary completion dates between 2013 and 2019. We then attempted to match each with a supporting P2 trial using strict and broad criteria. P3 outcomes were meta-analyzed using a random effects model with subgroup contrast between trials that bypassed and those that did not. 129 P3 trial arms met eligibility and nearly half involved P2 bypass. P3 trials involving P2 bypass produced significantly and nonsignificantly worse pooled efficacy estimates using broad and strict matching criteria, respectively. We did not observe significant differences in safety outcomes between P3 trials that bypassed P2 and those that did not. The risk/benefit balance of P3 trials that bypassed P2 is less favourable than for trials supported by P2.

Background. When combined with ceftazidime, the novel non–β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). Methods. The primary end point was clinical cure at test-of-cure visit 28–35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of −12.5%. Results. Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, −3.5%; 95% confidence interval −8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (−2.4%; −6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (−0.8%; −4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. Conclusions. Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone. Clinical Trials Registration. NCT01499290 and NCT01500239.

Alzheimer’s disease (AD) is a chronic disabling disease that affects the central nervous system. The main consequences of AD include the decline of cognitive functions and language disorders. One of the causes leading to AD is the decrease of neurotransmitter acetylcholine (ACh) levels in the brain, in part due to a higher activity of acetylcholinesterase (AChE), the enzyme responsible for its degradation. Many acetylcholinesterase inhibitors (AChEIs), both natural and synthetic, have been developed and used through the years to counteract the progression of the disease. The first of such drugs approved for a therapeutic use was tacrine, that binds through a reversible bond to the enzyme. However, tacrine has since been withdrawn because of its adverse effects. Currently, donepezil and galantamine are very promising AChEIs with clinical benefits. Moreover, rivastigmine is considered a pseudo-irreversible compound with anti-AChE action, providing similar effects at the clinical level. The purpose of this review is to provide an overview of what has been published over the last decade on the effectiveness of AChEIs in AD, analysing the most relevant issues under the clinical and methodological profiles and the consequent possible welfare effects for the whole world. Furthermore, novel drugs and possible therapeutic approaches are also discussed.