Explore the vast range of titles available.

Hereditary transthyretin amyloidosis is caused by the deposition of misfolded transthyretin proteins in peripheral nerves and other tissues. This phase 3 trial tested patisiran, a small interfering RNA targeting transthyretin messenger RNA, to treat the disease.

Casirivimab and imdevimab are non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells. We aimed to evaluate the efficacy and safety of casirivimab and imdevimab administered in combination in patients admitted to hospital with COVID-19. RECOVERY is a randomised, controlled, open-label platform trial comparing several possible treatments with usual care in patients admitted to hospital with COVID-19. 127 UK hospitals took part in the evaluation of casirivimab and imdevimab. Eligible participants were any patients aged at least 12 years admitted to hospital with clinically suspected or laboratory-confirmed SARS-CoV-2 infection. Participants were randomly assigned (1:1) to either usual standard of care alone or usual care plus casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion. Investigators and data assessors were masked to analyses of the outcome data during the trial. The primary outcome was 28-day all-cause mortality assessed by intention to treat, first only in patients without detectable antibodies to SARS-CoV-2 infection at randomisation (ie, those who were seronegative) and then in the overall population. Safety was assessed in all participants who received casirivimab and imdevimab. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Between Sept 18, 2020, and May 22, 2021, 9785 patients enrolled in RECOVERY were eligible for casirivimab and imdevimab, of which 4839 were randomly assigned to casirivimab and imdevimab plus usual care and 4946 to usual care alone. 3153 (32%) of 9785 patients were seronegative, 5272 (54%) were seropositive, and 1360 (14%) had unknown baseline antibody status. 812 (8%) patients were known to have received at least one dose of a SARS-CoV-2 vaccine. In the primary efficacy population of seronegative patients, 396 (24%) of 1633 patients allocated to casirivimab and imdevimab versus 452 (30%) of 1520 patients allocated to usual care died within 28 days (rate ratio [RR] 0·79, 95% CI 0·69–0·91; p=0·0009). In an analysis of all randomly assigned patients (regardless of baseline antibody status), 943 (19%) of 4839 patients allocated to casirivimab and imdevimab versus 1029 (21%) of 4946 patients allocated to usual care died within 28 days (RR 0·94, 95% CI 0·86–1·02; p=0·14). The proportional effect of casirivimab and imdevimab on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity=0·002). There were no deaths attributed to the treatment, or meaningful between-group differences in the pre-specified safety outcomes of cause-specific mortality, cardiac arrhythmia, thrombosis, or major bleeding events. Serious adverse reactions reported in seven (<1%) participants were believed by the local investigator to be related to treatment with casirivimab and imdevimab. In patients admitted to hospital with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline. UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Patisiran (ONPATTRO™) is a double-stranded small interfering RNA encapsulated in a lipid nanoparticle for delivery to hepatocytes. By specifically binding to a genetically conserved sequence in the 3′ untranslated region of mutant and wild-type transthyretin (TTR) messenger RNA, patisiran causes its degradation (via RNA interference) and subsequently a reduction in serum TTR protein levels and tissue TTR protein deposits. Patisiran has been developed by Alnylam Pharmaceuticals; it was recently approved in the USA for the treatment of the polyneuropathy of hereditary TTR-mediated amyloidosis (hATTR) in adults and subsequently approved in the EU for the treatment of hATTR in adults with stage 1 or 2 polyneuropathy. The recommended dosage, administered as a single intravenous infusion over approximately 80 min, is 0.3 mg/kg once every 3 weeks for patients weighing < 100 kg and 30 mg once every 3 weeks for patients weighing ≥ 100 kg. This article summarizes the milestones in the development of patisiran leading to these approvals.

Carbapenem-resistant Gram-negative bacteria represent the highest priority for addressing global antibiotic resistance. Cefiderocol (S-649266), a new siderophore cephalosporin, has broad activity against Enterobacteriaceae and non-fermenting bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, including carbapenem-resistant strains. We assessed the efficacy and safety of cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-negative infections. We did a phase 2, multicentre, double-blind, parallel-group non-inferiority trial at 67 hospitals in 15 countries. Adults (≥18 years) admitted to hospital with a clinical diagnosis of complicated urinary tract infection with or without pyelonephritis or those with acute uncomplicated pyelonephritis were randomly assigned (2:1) by an interactive web or voice response system to receive 1 h intravenous infusions of cefiderocol (2 g) or imipenem-cilastatin (1 g each) three times daily, every 8 h for 7–14 days. Patients were excluded if they had a baseline urine culture with more than two uropathogens, a fungal urinary tract infection, or pathogens known to be carbapenem resistant. The primary endpoint was the composite of clinical and microbiological outcomes at test of cure (ie, 7 days after treatment cessation), which was used to establish non-inferiority (15% and 20% margins) of cefiderocol versus imipenem-cilastatin. The primary efficacy analysis was done on a modified intention-to-treat population, which included all randomly assigned individuals who received at least one dose of study drug and had a qualifying Gram-negative uropathogen (≥1 × 105 colony-forming units [CFU]/mL). Safety was assessed in all randomly assigned individuals who received at least one dose of study drug, according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02321800. Between Feb 5, 2015, and Aug 16, 2016, 452 patients were randomly assigned to cefiderocol (n=303) or imipenem-cilastatin (n=149), of whom 448 patients (n=300 in the cefiderocol group; n=148 in the imipenem-cilastatin group) received treatment. 371 patients (n=252 patients in the cefiderocol group; n=119 patients in the imipenem-cilastatin group) had qualifying Gram-negative uropathogen (≥1 × 105 CFU/mL) and were included in the primary efficacy analysis. At test of cure, the primary efficacy endpoint was achieved by 183 (73%) of 252 patients in the cefiderocol group and 65 (55%) of 119 patients in the imipenem-cilastatin group, with an adjusted treatment difference of 18·58% (95% CI 8·23–28·92; p=0·0004), establishing the non-inferiority of cefiderocol. Cefiderocol was well tolerated. Adverse events occurred in 122 (41%) of 300 patients in the cefiderocol group and 76 (51%) of 148 patients in the imipenem-cilastatin group, with gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) the most common adverse events for both treatment groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group). Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing. Shionogi & Co Ltd, Shionogi Inc.

Patients with moderate-to-severe ulcerative colitis were randomly assigned to receive placebo or induction doses of ustekinumab. Patients who had a response to induction therapy underwent a second randomization to maintenance therapy with ustekinumab or placebo. Ustekinumab was more effective than placebo for inducing and maintaining remission.

Out-of-hospital cardiac arrest is a leading cause of death worldwide. Establishing vascular access is critical for administering guideline-recommended drugs during cardiopulmonary resuscitation. Both the intraosseous route and the intravenous route are used routinely, but their comparative effectiveness remains unclear. We conducted a randomized clinical trial to compare the effectiveness of initial attempts at intraosseous or intravenous vascular access in adults who had nontraumatic out-of-hospital cardiac arrest. The primary outcome was a sustained return of spontaneous circulation. Key secondary outcomes were survival at 30 days and survival at 30 days with a favorable neurologic outcome, defined by a score of 0 to 3 on the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability). Among 1506 patients who underwent randomization, 1479 were included in the primary analysis (731 in the intraosseous-access group and 748 in the intravenous-access group). The successful establishment of vascular access within two attempts occurred in 669 patients (92%) assigned to the intraosseous-access group and in 595 patients (80%) assigned to the intravenous-access group. Sustained return of spontaneous circulation occurred in 221 patients (30%) in the intraosseous-access group and in 214 patients (29%) in the intravenous-access group (risk ratio, 1.06; 95% confidence interval [CI], 0.90 to 1.24; P = 0.49). At 30 days, 85 patients (12%) in the intraosseous-access group and 75 patients (10%) in the intravenous-access group were alive (risk ratio, 1.16; 95% CI, 0.87 to 1.56); a favorable neurologic outcome at 30 days occurred in 67 patients (9%) and 59 patients (8%), respectively (risk ratio, 1.16; 95% CI, 0.83 to 1.62). Prespecified adverse events were uncommon. There was no significant difference in sustained return of spontaneous circulation between initial intraosseous and intravenous vascular access in adults who had out-of-hospital cardiac arrest. (Funded by the Novo Nordisk Foundation and others; IVIO EU Clinical Trials Register number, 2022-500744-38-00; ClinicalTrials.gov number, NCT05205031.).

PurposeTo determine the effects of the sodium content of maintenance fluid therapy on cumulative fluid balance and electrolyte disorders.MethodsWe performed a randomized controlled trial of adults undergoing major thoracic surgery, randomly assigned (1:1) to receive maintenance fluids containing 154 mmol/L (Na154) or 54 mmol/L (Na54) of sodium from the start of surgery until their discharge from the ICU, the occurrence of a serious adverse event or the third postoperative day at the latest. Investigators, caregivers and patients were blinded to the treatment. Primary outcome was cumulative fluid balance. Electrolyte disturbances were assessed as secondary endpoints, different adverse events and physiological markers as safety and exploratory endpoints.FindingsWe randomly assigned 70 patients; primary outcome data were available for 33 and 34 patients in the Na54 and Na154 treatment arms, respectively. Estimated cumulative fluid balance at 72 h was 1369 mL (95% CI 601–2137) more positive in the Na154 arm (p < 0.001), despite comparable non-study fluid sources. Hyponatremia < 135 mmol/L was encountered in four patients (11.8%) under Na54 compared to none under Na154 (p = 0.04), but there was no significantly more hyponatremia < 130 mmol/L (1 versus 0; p = 0.31). There was more hyperchloremia > 109 mmol/L under Na154 (24/35 patients, 68.6%) than under Na54 (4/34 patients, 11.8%) (p < 0.001). The treating clinicians discontinued the study due to clinical or radiographic fluid overload in six patients receiving Na154 compared to one patient under Na54 (excess risk 14.2%; 95% CI − 0.2–30.4%, p = 0.05).ConclusionsIn adult surgical patients, sodium-rich maintenance solutions were associated with a more positive cumulative fluid balance and hyperchloremia; hypotonic fluids were associated with mild and asymptomatic hyponatremia.

Background Recent studies have underscored the potential of innovative administration methods to mitigate the capacity burden on healthcare systems, without compromising the quality of care. This study assessed and compared the resource utilization and associated costs of two distinct administration modes of immune checkpoint inhibitors: the innovative elastomeric pump and conventional intravenous infusion. This comparison can inform sustainable healthcare practices and healthcare decision-making to optimize treatment efficiency in an era of escalating healthcare demands. Methods In this micro-costing study, data on resource use and time allocation for drug preparation and administration were collected using an observational, non-interventional study design. Data were registered at the oncology daycare unit and hospital pharmacy. Cost categories included drug acquisition, disposable materials, healthcare professional time for drug administration, drug preparation, and patient time spent at the oncology day care unit. Results Drug administration through the elastomeric pump resulted in substantially lower healthcare costs when compared to conventional infusion, particularly due to reduced labor and chair time. The elastomeric pump reduced the total chair time by 78% and nurse time by 55%. Total average costs (excluding drug costs) were €103,47 and €77.99 for conventional infusion and the elastomeric pump, respectively, showcasing potential savings of €25.48 ( P  < 0.001) per administration. Conclusions This study demonstrated that the elastomeric pump not only offers substantial cost savings but also enhances the treatment capacity of the oncology day care unit. These findings support the adoption of the elastomeric pump in clinical settings as a cost-saving and efficient alternative to conventional infusion. Trial registration This study has been registered in the National Trial Register (NTR), with the reference number NTR NL9473. Registration date: 05-05-2021.

In this 52-week randomized trial, the α 4 β 7 integrin antibody vedolizumab was effective in treating Crohn's disease. The incidence of serious adverse events was higher with vedolizumab than with placebo. Crohn's disease is a chronic inflammatory bowel disease. 1 Current treatments include glucocorticoids, immunosuppressive agents (i.e., azathioprine, mercaptopurine, or methotrexate), and tumor necrosis factor (TNF) antagonists. 1 – 3 Many patients do not have a response to therapy, 4 and treatments are associated with important toxic effects. 5 , 6 Natalizumab, a monoclonal antibody that modulates gut and brain lymphocyte migration by antagonizing α 4 β 1 and α 4 β 7 integrin–mediated interactions, 7 is efficacious in the treatment of multiple sclerosis 8 , 9 and Crohn's disease. 10 – 12 Its use in patients with Crohn's disease has been limited by the development in some patients of progressive multifocal . . .

In chronic kidney disease both renal insufficiency and chronic inflammation trigger elevated hepcidin levels, which impairs iron uptake, availability. and erythropoiesis. Here we report the two first-in-human phase 1 trials of PRS-080#22, a novel, rationally engineered Anticalin protein that targets and antagonizes hepcidin. A single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients with end stage chronic kidney disease (CKD) on hemodialysis (phase 1b) at different doses (0.08-16mg/kg for the phase 1a study and 2-8mg/kg for the phase 1b study) in successive dosing cohorts. The primary endpoint for both randomized, double-blind, phase 1 trials was safety and tolerability. Following treatment, all subjects were evaluable, with none experiencing dose limiting toxicities. Most adverse events were mild. One serious adverse event occurred in the phase 1b (CKD patient) study. There were no clinically significant changes in safety laboratory values or vital signs. PRS-080#22 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately three days in healthy volunteers and 10 to 12 days in CKD patients. Serum hepcidin levels were suppressed in a dose dependent manner and remained low for up to 48 hours after dosing. PRS-080#22 dose-dependently mobilized serum iron with increases in both serum iron concentration and transferrin saturation. No consistent changes were observed with regard to ferritin, reticulocytes, hemoglobin, and reticulocyte hemoglobin. Low titer anti-drug-antibodies were detected in five healthy volunteers but in none of the CKD patients. PRS-080#22, a novel Anticalin protein with picomolar affinity for hepcidin, was safe and well-tolerated when administered to healthy volunteers and CKD patients at all doses tested. The drug exhibited linear pharmacokinetics, longer half-life in CKD patients in comparison to healthy volunteers as well as expected pharmacodynamic effects which hold promise for further clinical studies.