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.

Project description:INTRODUCTION:Hospitalised patients with nasogastric/nasoenteric tube (NGT/NET) are at constant risk of incidents; therefore, healthcare professionals need to routinely monitor risks and adopt strategies for patient safety and quality of care. AIM:This study aimed to evaluate the NGT/NET-related incidents in hospitalised patients and associated factors. METHODS:This is a multicentre study, with a prospective cohort design. Data will be collected at the general medical ward of seven Brazilian hospitals in the north, northeast, southeast and south. The sample will consist of 391 patients that require an NGT/NET during hospitalisation. Three different methods will be used to identify the incidents: (1) healthcare professionals and patients/caregivers will be required to report any NGT/NET-related incidents; (2) researchers will visit the wards to get information about the incidents with healthcare professionals and patients/caregivers; (3) the researchers will review the medical records looking for information on the occurrence of any NGT/NET-related incidents. Demographic, clinical and therapeutic details will be obtained from the medical records and will be registered in an electronic data collection tool developed for the purposes of this study. The complexity of patients will be assessed by the Patient Classification System, and the severity of comorbid diseases will be assessed through the Charlson Comorbidity Index. IMPLICATION FOR PRACTICE:The results may encourage the use of evidence effectively to influence the scientific foundation for clinical practice and the development of evidence-based policies that will prevent, manage and eliminate complications caused by NGT/NET-related incidents, and improve the quality and safety of care provided to hospitalised patients. ETHICS AND DISSEMINATION:The study has been approved by the Research Ethics Committee. Detailed information about the study can be provided by the principal investigator. The findings will be reported through academic journals, seminar and conference presentations, social media, print media, the internet and community/stakeholder engagement activities.

Project description:ObjectivesTo determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection.Trial designASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management.ParticipantsParticipants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently.Intervention and comparatorParticipants will be randomised 1:1:1:1 to: Group 1: standard of care; Group 2: lopinavir (400mg) / ritonavir (100mg) twice daily for 10 days in tablet form; Group 3: hydroxychloroquine (800mg) 4x200mg administered 12 hours apart on Day 1, followed by 400mg twice a day for 6 days; Group 4: lopinavir /ritonavir plus hydroxychloroquine.Main outcomesProportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation) at 15 days after enrolment. A range of clinical and virological secondary outcomes will also be evaluated.RandomisationThe randomisation schedule will be generated by an independent statistician. Randomisation will be stratified by site and will be in permuted blocks of variable block size. The randomised sequence allocation will only be accessible to the data management group, and site investigators will have individual participant allocation provided through a web-based trial enrolment platform.Blinding (masking)This is an open-label study, with researchers assessing the laboratory outcomes blinded to treatment allocation. No unblinding procedures relating to potential adverse effects are therefore required.Numbers to be randomised (sample size)We assumed that 5% of participants receiving standard of care would meet the primary outcome, aimed to evaluate whether interventions could lead to a relative risk of 0.5, assuming no interaction between intervention arms. This corresponds to a required sample size of 610 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total sample size therefore is planned to be 2440.Trial statusASCOT protocol version 3, May 5, 2020. Recruitment opened April 4, 2020 and is ongoing, with planned completion of enrolment July 31, 2021.Trial registrationAustralian New Zealand Clinical Trials Registry ( ACTRN12620000445976 ). Prospectively registered April 6, 2020.Full protocolThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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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