Mobilizing the clinical trial ecosystem to drive adoption of master protocols.

Master protocol studies typically use an overarching protocol to answer several questions by guiding a variety of sub-studies. These sub-studies can incorporate multiple diseases, therapies, or both. Although this innovative approach offers many benefits, including the ability to deliver clinical research that is more patient-centric and efficient, several common barriers curtail widespread adoption. The Clinical Trials Transformation Initiative (CTTI) convened industry representatives, regulatory agencies, patient groups, and academic institutions to identify emerging best practices and develop resources designed to help sponsors and other stakeholders overcome these challenges. We first identify some broad changes needed in the clinical trials ecosystem to facilitate mainstream adoption of master protocol studies, and we subsequently summarize CTTI's resources designed to support this effort.

Comparison of the platelet activation status of single-donor platelets obtained with two different cell separator technologies.

BACKGROUND: The microparticle content (MP%) of apheresis platelets-a marker of platelet activation-is influenced by donor factors and by external stressors during collection and storage. This study assessed the impact of apheresis technology and other factors on the activation status (MP%) of single-donor apheresis platelets. STUDY DESIGN AND METHODS: Data from six US hospitals that screened platelets by measuring MP% through dynamic light scattering (ThromboLUX) were retrospectively analyzed. Relative risks (RRs) were derived from univariate and multivariable regression models, with activation rate (MP% ≥15% for plasma-stored platelets; ≥10% for platelet additive solution [PAS]-stored platelets) and MP% as outcomes. Apheresis platform (Trima Accel vs Amicus), storage medium (plasma vs PAS), pathogen reduction, storage time, and testing location were used as predictors. RESULTS: Data were obtained from 7511 platelet units collected using Trima (from 16 suppliers, all stored in plasma, 20.0% were pathogen-reduced) and 2456 collected using Amicus (from four different collection facilities of one supplier, 65.0% plasma-stored, 35.0% PAS-stored, none pathogen-reduced). Overall, 30.0% of Trima platelets were activated compared to 45.6% of Amicus platelets (P < .0001). Multivariable analysis identified apheresis platform as significantly associated with platelet activation, with a lower activation rate for Trima than Amicus (RR: 0.641, 95% confidence interval [CI]: 0.578; 0.711, P < .0001) and a 6.901% (95% CI: 5.926; 7.876, P < .0001) absolute reduction in MP%, when adjusting for the other variables. CONCLUSION: Trima-collected platelets were significantly less likely to be activated than Amicus-collected platelets, irrespective of the storage medium, the use of pathogen reduction, storage time, and testing site.

Screening of red blood cells for extracellular vesicle content as a product quality indicator.

BACKGROUND: The controversy around the quality and clinical impact of stored and differentially manufactured red cell concentrates (RCCs) from different donor groups is ongoing. Current studies are limited by the lack of quality measures suitable for routine screening of RCCs. As extracellular vesicles (EVs) are markers of cellular activation or degradation, this study investigated the utility of EV screening to characterize the effects of RBCs production methods and storage. STUDY DESIGN AND METHODS: RCCs were prepared by whole blood filtration or red blood cell (RBC) filtration methods, centrifuged to prepare a supernatant, and tested for EV content (dynamic light scattering or tunable resistive pulse-sensing techniques), hemolysis, ATP, and RBC deformability on Days 7, 21, and 42 of storage. To simulate nondestructive quality control (QC) testing, 1 RBC unit was tested in parallel with six 10-mL aliquots that were stored in small-volume containers. RESULTS: EV content showed a linear increase with storage time (p < 0.001) and correlated with supernatant hemoglobin and inversely with ATP or RBC deformability. The method of component manufacturing influenced the characteristics of the EVs during storage. A strong correlation between both EV testing methods' measure of total EV was observed. EV content in the six aliquots were consistent at each time point but statistically higher than in the original RCCs on and after 21 days of storage. CONCLUSIONS: EV content correlates with measures of hemolysis and other RBC quality indicators and could be implemented as a routine screening tool for nondestructive QC testing of RCCs.

Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL.

Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Routine Screening Method for Microparticles in Platelet Transfusions.

Platelet inventory management based on screening microparticle content in platelet concentrates is a new quality improvement initiative for hospital blood banks. Cells fragment off microparticles (MP) when they are stressed. Blood and blood components may contain cellular fragments from a variety of cells, most notably from activated platelets. When performing their roles as innate immune cells and major players in coagulation and hemostasis, platelets change shape and generate microparticles. With dynamic light scattering (DLS)-based microparticle detection, it is possible to differentiate activated (high microparticle) from non-activated (low microparticle) platelets in transfusions, and optimize the use of this scarce blood product. Previous research suggests that providing non-activated platelets for prophylactic use in hematology-oncology patients could reduce their risk of becoming refractory and improve patient care. The goal of this screening method is to routinely differentiate activated from non-activated platelets. The method described here outlines the steps to be performed for routine platelet inventory management in a hospital blood bank: obtaining a sample from a platelet transfusion, loading the sample into the capillary for DLS measurement, performing the DLS test to identify microparticles, and using the reported microparticle content to identify activated platelets.

Oral ivermectin for treatment of pediculosis capitis.

BACKGROUND: Pediculosis capitis is a highly transmissible infestation prevalent worldwide. It is an important public health problem mainly affecting children. The emergence of drug resistance and high rates of treatment failure with several topical agents makes ivermectin, an antiparasitic drug, an attractive therapeutic option for lice control. OBJECTIVE: To evaluate the efficacy and safety of oral ivermectin in the treatment of a pediatric population with pediculosis capitis. METHODS: Children with pediculosis capitis from the ages of 6 to 15 years were recruited from an indigenous community in Mexico, and were treated with a single dose of oral ivermectin at 200 µg/kg. They were treated with a second dose of ivermectin 1 week later if there was evidence of persistent infestation. RESULTS: Forty-four children (mean age, 9.8 years) with active infestation were treated. A single approximately 200-µg/kg dose of ivermectin eradicated adult lice in all children. Forty-one percent (n = 18) required a second dose because of the presence of viable nits. At the third visit, 2 weeks after commencement of treatment there was no evidence of viable nits, and there was complete resolution of excoriations in all children and minimal or no symptoms of pruritus were reported in 93% (n = 41). There were no significant adverse effects due to ivermectin administration. CONCLUSIONS: Ivermectin demonstrates high efficacy and tolerability in the treatment of pediculosis capitis in children. A significant number of children required a second dose to ensure complete eradication.