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.

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.

Project description:ObjectivesOpioid-induced respiratory depression (OIRD) and oversedation are rare but potentially devastating adverse events in hospitalised patients. We investigated which features predict an individual patient's risk of OIRD or oversedation; and developed a risk stratification tool that can be used to aid point-of-care clinical decision-making.DesignRetrospective observational study.SettingTwelve acute care hospitals in a large not-for-profit integrated delivery system.ParticipantsAll inpatients ≥18 years admitted between 1 July 2016 and 30 June 2018 who received an opioid during their stay (163 190 unique hospitalisations).Main outcome measuresThe primary outcome was occurrence of sedation or respiratory depression severe enough that emergent reversal with naloxone was required, as determined from medical record review; if naloxone reversal was unsuccessful or if there was no evidence of hypoxic encephalopathy or death due to oversedation, it was not considered an oversedation event.ResultsAge, sex, body mass index, chronic obstructive pulmonary disease, concurrent sedating medication, renal insufficiency, liver insufficiency, opioid naïvety, sleep apnoea and surgery were significantly associated with risk of oversedation. The strongest predictor was concurrent administration of another sedating medication (adjusted HR, 95% CI=3.88, 2.48 to 6.06); the most common such medications were benzodiazepines (29%), antidepressants (22%) and gamma-aminobutyric acid analogue (14.7%). The c-statistic for the final model was 0.755. The 24-point Oversedation Risk Criteria (ORC) score developed from the model stratifies patients as high (>20%, ≥21 points), moderate (11%-20%, 10-20 points) and low risk (≤10%, <10 points).ConclusionsThe ORC risk score identifies patients at high risk for OIRD or oversedation from routinely collected data, enabling targeted monitoring for early detection and intervention. It can also be applied to preventive strategies-for example, clinical decision support offered when concurrent prescriptions for opioids and other sedating medications are entered that shows how the chosen combination impacts the patient's risk.

Dataset Information

ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial.

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