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Expanding the indication of already approved immuno-oncology drugs presents treatment opportunities for patients but also strains healthcare systems. Cost-based pricing models are discussed as a possibility for cost containment. This study focuses on two drugs, pembrolizumab (Keytruda) and daratumumab (Darzalex), to explore the potential effect of indication broadening on the estimated price when using the cost-based pricing (CBP) model proposed by Uyl-de Groot and Löwenberg (2018). The model was used to calculate cumulative yearly prices, cumulative prices per indication, and non-cumulative indication-based prices using inputs such as research and development (R&D) costs, manufacturing costs, eligible patient population, and a profit margin. A deterministic stepwise analysis and scenario analysis were conducted to examine how sensitive the estimated price is to the different input assumptions. The yearly cumulative cost-based prices (CBPs) ranged from €52 to €885 for pembrolizumab per vial and €823 to €31,941 for daratumumab per vial. Prices were higher in initial years or indications due to smaller patient populations, decreased over time or after additional indications. Sensitivity analysis showed that the number of eligible patients had the most significant impact on the estimated price. In the scenario analysis the profit margin contributed most to a higher CBPs for both drugs. Lower estimates resulted from assumed lower R&D costs. The estimated CBPs are consistently lower than Dutch list prices for pembrolizumab (€2,861), mainly resulting from larger patient populations in registered indications. However, daratumumab's list prices fall within the range of modeled CBPs depending on the year or indication (€4,766). Both CBPs decrease over time or with additional indications. The number of eligible patients and initial R&D costs have the most significant influence on the CBPs. These findings contribute to the ongoing discussions on pharmaceutical pricing, especially concerning cancer drugs with expanding indications.

Background In economic evaluations, survival is often extrapolated to smooth out the Kaplan-Meier estimate and because the available data (e.g., from randomized controlled trials) are often right censored. Validation of the accuracy of extrapolated results can depend on the length of follow-up and the assumptions made about the survival hazard. Here, we analyze the accuracy of different extrapolation techniques while varying the data cut-off to estimate long-term survival in newly diagnosed multiple myeloma (MM) patients. Methods Empirical data were available from a randomized controlled trial and a registry for MM patients treated with melphalan + prednisone, thalidomide, and bortezomib- based regimens. Standard parametric and spline models were fitted while artificially reducing follow-up by introducing database locks. The maximum follow-up for these locks varied from 3 to 13 years. Extrapolated (conditional) restricted mean survival time (RMST) was compared to the Kaplan-Meier RMST and models were selected according to statistical tests, and visual fit. Results For all treatments, the RMST error decreased when follow-up and the absolute number of events increased, and censoring decreased. The decline in RMST error was highest when maximum follow-up exceeded six years. However, even when censoring is low there can still be considerable deviations in the extrapolated RMST conditional on survival until extrapolation when compared to the KM-estimate. Conclusions We demonstrate that both standard parametric and spline models could be worthy candidates when extrapolating survival for the populations examined. Nevertheless, researchers and decision makers should be wary of uncertainty in results even when censoring has decreased, and the number of events has increased.

Background Sepsis and septic shock are significant global healthcare challenges with high mortality rates. Effective management requires timely and adequate antimicrobial therapy. Beta-lactam antibiotics, commonly used in patients with sepsis, are crucial for treating these infections. However, standard dosing often leads to insufficient plasma levels due to dynamic physiological changes in critically ill patients. Previous randomized controlled trials highlighted the need for timely dose adjustments to improve clinical outcomes. This is the study protocol for the BULLSEYE trial in which we aim to optimize antibiotic treatment during the initial 48 h of sepsis by comparing standard to double dosing of beta-lactam antibiotics. Methods This open-label, multicenter, randomized controlled trial will compare standard to double dosing of beta-lactam antibiotics (cefuroxime, ceftazidime, ceftriaxone, cefotaxime, amoxicillin, amoxicillin/clavulanic acid, flucloxacillin, meropenem, and piperacillin/clavulanic acid) in critically ill patients with septic shock. Participants will be randomized into two arms: the control arm receiving standard care, and the intervention arm receiving double antibiotic doses for 48 h, irrespective of renal function. Following this period, all patients will receive standard doses as per local protocol. The primary outcome is all cause 28-day mortality, with secondary outcomes including 90-day, 365-day, hospital and ICU mortality, hospital and ICU length of stay, SOFA scores, time to shock reversal, microbiological eradication, clinical cure, pharmacodynamic target attainment, safety, quality of life, and medical consumption. Discussion The BULLSEYE trial aims to improve sepsis treatment in critically ill patients. Despite anticipated recruitment challenges, its large sample size ensures robust comparability. This pivotal trial could significantly impact sepsis treatment, leading to better clinical outcomes. Trial registration EU_CT 2024–512950-13–00. Protocol version 2.3, protocol date 09–12-2024. Prospectively registered on 09–01-2025 at Clinicaltrails.gov nr. NCT06766461.

Burkitt lymphoma is an aggressive B cell malignancy accounting for 1–2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14–74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.

In a trial comparing the addition of clopidogrel with no clopidogrel in patients receiving anticoagulation, the incidence of any bleeding and of non–procedure-related bleeding was lower in the monotherapy group. Composite cardiovascular outcomes were noninferior for the monotherapy group but were superior only for a composite that included bleeding.

In patients undergoing transcatheter aortic-valve implantation, aspirin alone was associated with fewer bleeding events than aspirin plus clopidogrel administered for 3 months and was noninferior to the combination therapy with respect to thrombotic events.

IntroductionStandard premedication for paclitaxel-based chemotherapy includes dexamethasone and an histamine 1-antagonist to prevent hypersensitivity reactions (HSRs). However, the pharmacological rationale for dexamethasone is limited, and its use is associated with adverse effects such as hyperglycaemia, insomnia and immunodeficiency, negatively impacting health-related quality of life (HRQoL). No clear link has been established between dexamethasone dose, administration route and HSR incidence. Previous studies suggest that discontinuing dexamethasone beyond the second administration does not increase HSR risk. Despite this, dexamethasone remains standard practice. This trial evaluates whether complete omission of dexamethasone as paclitaxel premedication is non-inferior to the standard regimen in preventing clinically relevant HSRs (Common Terminology Criteria for Adverse Events (CTCAE) grade≥3).MethodsThe DEXASTOP trial is a prospective, multicentre, randomised, non-inferiority study conducted in four hospitals in the Netherlands. 500 adult patients receiving paclitaxel-based chemotherapy for any solid tumour indication will be randomised 1:1 to receive either standard premedication with dexamethasone or an experimental regimen without dexamethasone for up to five paclitaxel administrations. The primary endpoint is the incidence of clinically relevant HSRs (CTCAE grade≥3). Secondary endpoints include the incidence and severity of all-grade HSRs, the number of paclitaxel administrations before the first HSR, dexamethasone-related adverse events, HRQoL and cost-effectiveness from a healthcare and societal perspective.Ethics and disseminationThis study has been approved by the Erasmus Medical Centre Ethics Committee (reference MEC-2024-0030, protocol version 3, May 2024). Study findings will be published open access in peer-reviewed journals and presented at national and international meetings. Results will be shared with patients, healthcare professionals and the public. Positive outcomes will be implemented in clinical practice, and trial data will be submitted to the EU Clinical Trials Information System for public access.Trial registration numberNCT06118710.

Currently, no oral medications are available for type 1 diabetes (T1D). While our recent randomized placebo-controlled T1D trial revealed that oral verapamil had short-term beneficial effects, their duration and underlying mechanisms remained elusive. Now, our global T1D serum proteomics analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the top protein altered by verapamil and as a potential therapeutic marker and revealed that verapamil normalizes serum CHGA levels and reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cell markers. RNA-sequencing further confirmed that verapamil regulates the thioredoxin system and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta-cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D. Oral verapamil lowers inflammatory markers and daily insulin needs in subjects with type 1 diabetes and helps preserve pancreatic beta cell function for at least two years. In this context, serum chromogranin A provides a promising therapy marker.

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.