Efficient adaptive designs for clinical trials of interventions for COVID-19 Presenting features of COVID-19 in older people: relationships with frailty, inflammation and mortality

The COVID-19 pandemic has led to an unprecedented response in terms of clinical research activity An important part of this research has been focused on randomized controlled clinical trials to evaluate potential therapies for COVID-19 The results from this research need to be obtained as rapidly as possible This presents a number of challenges associated with considerable uncertainty over the natural history of the disease and the number and characteristics of patients affected, and the emergence of new potential therapies These challenges make adaptive designs for clinical trials a particularly attractive option Such designs allow a trial to be modified on the basis of interim analysis data or stopped as soon as sufficiently strong evidence has been observed to answer the research question, without compromising the trial's scientific validity or integrity In this paper we describe some of the adaptive design approaches that are available and discuss particular issues and challenges associated with their use in the pandemic setting Our discussion is illustrated by details of four ongoing COVID-19 trials that have used adaptive designs Purpose To describe the clinical features of COVID-19 in older adults, and relate these to outcomes Methods Cohort study of 217 individuals (≥70 years) hospitalised with COVID-19, followed ufor allcause mortality Secondary outcomes included cognitive and physical function at discharge C-reactive protein and neutrophil : lymphocyte ratio were used as measures of immune activity Results Cardinal COVID-19 symptoms (fever, dyspnoea, cough) were common but not universal Inflammation on hospitalisation was lower in frail older adults Fever, dyspnoea, delirium and inflammation were associated with mortality Delirium at presentation was an independent risk factor for cognitive decline at discharge Conclusions COVID-19 may present without cardinal symptoms as well as implicate a possible role for agerelated changes in immunity in mediating the relationshibetween frailty and mortality Competing Interest StatementThe authors have declared no competing interest Funding StatementDaniel Davis is funded through a Wellcome Intermediate Clinical Fellowshi(WT107467) Author Declarationsconfirm all relevant ethical guidelines have been followed, and any necessary IRand/or ethics committee approvals have been obtained YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:These analyses were conducted as part of a service evaluation project and individual consent was not necessary as determined by the NHS Health Research Authority (HRA), the regulatory body for medical research for England, UK The HRA has the Research Ethics Service as one of its core functions and they determined the project was exempt from the need to obtain approval from an NHS Research Ethics Committee https://www hra nhs uk/about-us/committees-and-services/res-and-recs/All necessary patientarticipant consent has been obtained and the appropriate institutional forms have been archived Yesunderstand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials gov confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance) Yes have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable YesOn request