AGILE-ACCORD: A Randomized, Multicentre, Seamless, Adaptive Phase I/II Platform Study to Determine the Optimal Dose, Safety and Efficacy of Multiple Candidate Agents for the Treatment of COVID-19: A structured summary of a study protocol for a randomised platform trial.
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SUBMITTER: Griffiths G
PROVIDER: S-EPMC7303573 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThere is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions.Methods/designAGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol.DiscussionFew approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment.Trial registrationEudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183 19 February 2021 ISRCTN reference: 27106947.
| S-EPMC8311065 | biostudies-literature
Project description: Not available
| S-EPMC7393340 | biostudies-literature
Project description:The coiled-coil (CC) domain is a very important structural unit of proteins that plays critical roles in various biological functions. The major oligomeric state of CCs is a dimer, which can be either parallel or antiparallel. The orientation of each α-helix in a CC domain is critical for the molecular function of CC-containing proteins, but cannot be determined easily by sequence-based prediction. We developed a biochemical method for assessing differences between parallel and antiparallel CC homodimers and named it ACCORD (Assessment tool for homodimeric Coiled-Coil ORientation Decision). To validate this technique, we applied it to 15 different CC proteins with known structures, and the ACCORD results identified these proteins well, especially with long CCs. Furthermore, ACCORD was able to accurately determine the orientation of a CC domain of unknown directionality that was subsequently confirmed by X-ray crystallography and small angle X-ray scattering. Thus, ACCORD can be used as a tool to determine CC directionality to supplement the results of in silico prediction.
| S-EPMC5339707 | biostudies-literature
Project description:The emerging technique termed functional identification of target by expression proteomics (FITExP) has been shown to identify the key protein targets of anti-cancer drugs. Here, we use this approach to elucidate the proteins involved in the mechanism of action of two ruthenium(II)-based anti-cancer compounds, RAPTA-T and RAPTA-EA in breast cancer cells, revealing significant differences in the proteins upregulated. RAPTA-T causes upregulation of multiple proteins suggesting a broad mechanism of action involving suppression of both metastasis and tumorigenicity. RAPTA-EA bearing a GST inhibiting ethacrynic acid moiety, causes upregulation of mainly oxidative stress related proteins. The approach used in this work could be applied to the prediction of effective drug combinations to test in cancer chemotherapy clinical trials.
| S-EPMC5431558 | biostudies-literature
Project description:BACKGROUND: Summary measures of health that combine mortality and morbidity into a single indicator are being estimated in the Canadian context for approximately 200 diseases and conditions. To manage the large amount of data and calculations for this many diseases, we have developed a structured workbook system with easy to use tools. We expect this system will be attractive to researchers from other countries or regions of Canada who are interested in estimating the health-adjusted life years (HALYs) lost to premature mortality and year-equivalents lost to reduced functioning, as well as population attributable fractions (PAFs) associated with risk factors. This paper describes the workbook system using cancers as an example, and includes the entire system as a free, downloadable package. METHODS: The workbook system was developed in Excel and runs on a personal computer. It is a database system that stores data on population structure, mortality, incidence, distributions of cases entering a multitude of health states, durations of time spent in health states, preference scores that weight for severity, life table estimates of life expectancies, and risk factor prevalence and relative risks. The tools are Excel files with embedded macro programs. The main tool generates workbooks that estimate HALY, one per disease, by copying data from the database into a pre-defined template. Other tools summarize the HALY results across diseases for easy analysis. RESULTS: The downloadable zip file contains the database files initialized with Canadian data for cancers, the tools, templates and workbooks that estimate PAF and a user guide. The workbooks that estimate HALY are generated from the system at a rate of approximately one minute per disease. The resulting workbooks are self-contained and can be used directly to explore the details of a particular disease. Results can be discounted at different rates through simple parameter modification. CONCLUSION: The structured workbook approach offers researchers an efficient, easy to use, and easy to understand set of tools for estimating HALY and PAF summary measures for their country or region of interest.
| S-EPMC1156945 | biostudies-literature
Project description: Not available
| S-EPMC7388426 | biostudies-literature
Project description:BackgroundOperations require collaboration between surgeons, anaesthetia professionals, and nurses. The aim of this study was to determine whether intraoperative briefings influence patient outcomes.MethodsIn a before-and-after controlled trial (9 months baseline; 9 months intervention), intraoperative briefings were introduced in four general surgery centres between 2015 and 2018. During the operation, the responsible surgeon (most senior surgeon present) briefed the surgical team using the StOP? protocol about: progress of the operation (Status), next steps (Objectives), possible problems (Problems), and encouraged asking questions (?). Differences between baseline and intervention were analysed regarding surgical-site infections (primary outcome), mortality, unplanned reoperations, and duration of hospital stay (secondary outcomes), using inverse probability of treatment (IPT) weighting based on propensity scores.ResultsIn total, 8256 patients underwent surgery in the study. Endpoint data were available for 7745 patients (93.8 per cent). IPT-weighted and adjusted intention-to-treat analyses showed no differences in surgical-site infections between baseline and intervention (9.8 versus 9.6 per cent respectively; adjusted difference (AD) -0.15 (95 per cent c.i. -1.45 to 1.14) per cent; odds ratio (OR) 0.92, 95 per cent c.i. 0.83 to 1.15; P = 0.797), but there were reductions in mortality (1.6 versus 1.1 per cent; AD -0.54 (-1.04 to -0.03) per cent; OR 0.60, 0.39 to 0.92; P = 0.018), unplanned reoperations (6.4 versus 4.8 per cent; AD -1.66 (-2.69 to -0.62) per cent; OR 0.72, 0.59 to 0.89; P = 0.002), and fewer prolonged hospital stays (21.6 versus 19.8 per cent; AD -1.82 (-3.48 to -0.15) per cent; OR 0.87, 0.77 to 0.98; P = 0.024).ConclusionShort intraoperative briefings improve patient outcomes and should be performed routinely.
| S-EPMC10401893 | biostudies-literature
Project description:Advances in stem cell engineering, gene therapy and molecular medicine often involve genome engineering at a cellular level. However, functionally large or multi transgene cassette insertion into the human genome still remains a challenge. Current practices such as random transgene integration or targeted endonuclease-based genome editing are suboptimal and might pose safety concerns. Taking this into consideration, we previously developed a transgenesis tool derived from phage λ integrase (Int) that precisely recombines large plasmid DNA into an endogenous sequence found in human Long INterspersed Elements-1 (LINE-1). Despite this advancement, biosafety concerns associated with bacterial components of plasmids, enhanced uptake and efficient transgene expression remained problematic. We therefore further improved and herein report a more superior Int-based transgenesis tool. This novel Int platform allows efficient and easy derivation of sufficient amounts of seamless supercoiled transgene vectors from conventional plasmids via intramolecular recombination as well as subsequent intermolecular site-specific genome integration into LINE-1. Furthermore, we identified certain LINE-1 as preferred insertion sites for Int-mediated seamless vector transgenesis, and showed that targeted anti-CD19 chimeric antigen receptor gene integration achieves high-level sustained transgene expression in human embryonic stem cell clones for potential downstream therapeutic applications.
| S-EPMC6144826 | biostudies-literature
Project description:Most of previous studies investigated the optimal control of HIV infection at either within-host or between-host level. However, the optimal treatment strategy for the individual may not be optimal for the population and vice versa. To determine when the two-level optimal controls are in accord or conflict, we develop a multi-scale model using various functions that link the viral load within host and the transmission rate between hosts, calibrated by cohort data. We obtain the within-host optimal treatment scheme that minimizes the viral load and maximizes the count of healthy cells at the individual level, and the coupled optimal scheme that minimizes the basic reproduction number at the population level. Mathematical analysis shows that whether the two-level optimal controls coincide depends on the sign of the product of their switching functions. Numerical results suggest that they are in accord for a high maximal drug efficacy but may conflict for a low drug efficacy. Using the multi-scale model, we also identify a threshold of the treatment effectiveness that determines how early treatment initiation can affect the disease dynamics among population. These results may help develop a synergistic treatment protocol beneficial to both HIV-infected individuals and the whole population.
| S-EPMC10826718 | biostudies-literature
Project description:These research areas concentrate on stress induced proteases in recombinant Escherichia coli, glycosylation heterogeneity due to bioprocess conditions produced in mammalian cells, and metabolic engineering of E. coli. The hypothesis of this project is that recombinant protein glycosylation is inefficient under normal bioreactor conditions since the additional glycosylation reactions necessary for the recombinant protein exceed the metabolic capacity of the cells. Normal bioreactor conditions have been optimized for cell growth, and sometimes for protein productivity. Only recently has it been accepted that optimal glycosylation may not occur under optimal growth or protein productivity conditions. Specific Aim: Determine the relationship between bioreactor conditions and glycosylation gene expression in NS0 cells.
2011-04-29 | GSE28920 | GEO