Scottish Index of Multiple Deprivation (SIMD) Indicators as Predictors of Mortality Among Patients Hospitalised with COVID-19 Disease in the Lothian Region, Scotland During the First Wave: A Cohort Study (preprint)

Background: Sars-CoV-2, the causative agent of COVID-19, has led to more than 100,000 deaths in the UK and multiple risk factors for mortality including age, sex and deprivation have been identified. This study aimed to identify which indicators of Scottish Index of Multiple Deprivation (SIMD), an area-based deprivation index, were predictive of mortality. Methods: This was a prospective cohort study of anonymised electronic health records of 710 consecutive patients hospitalised with Covid-19 disease between March and June 2020 in the Lothian Region of Southeast Scotland. Data sources included automatically extracted data from national electronic platforms and manually extracted data from individual admission records. Exposure variables of interest were SIMD quintiles and more specifically 12 indicators of deprivation deemed clinically relevant selected from the SIMD. Our primary outcome was mortality. Univariable and multivariable logistic regression analyses adjusted for age and sex were used to determine measures of association between exposures of interest and the primary outcome. Results: After adjusting for age and sex, we found an increased risk of mortality in the more deprived SIMD quintiles 1 and 3 (OR 1.75, CI 0.99-3.08, p=0.053 and OR 2.17, CI 1.22-3.86, p=0.009, respectively), but this association was not significant in our multivariable model adjusted for co-morbidities and clinical parameters of severity at admission. Of the 12 pre-selected indicators of deprivation, two were associated with greater mortality in our multivariable analysis: income deprivation rate categorised by quartile (Q4 (most deprived): 2.11 (1.20-3.77) p=0.011)) and greater than expected hospitalisations due to alcohol per SIMD data zone (1.96 (1.28-3.00) p=0.002)). Conclusions: In contrast to other studies, deprivation quintile distribution was not predictive of mortality in our cohort. This possibly reflects the greater affluence and ethnic homogeneity of the Lothian Region compared to the rest of Scotland. We identified an increased risk of mortality in patients residing in areas with greater income-deprivation and/or number of hospitalisations due to alcohol. In areas where aggregate measures fail to capture pockets of deprivation, specific indicators may be helpful in targeting resources to residents at risk of poorer outcomes from Covid-19.

Randomised Controlled Trial of Intravenous Nafamostat Mesylate in COVID Pneumonitis: Phase 1b/2a Experimental Study to Investigate Safety, Pharmacokinetics and Pharmacodynamics (preprint)

Background: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is Nafamostat Mesylate.Methods: We present the findings of a phase Ib/II open label, platform randomised controlled trial of intravenous Nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), Nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2mg/kg/hour for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC.Results: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous Nafamostat. 78% of Nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The Nafamostat group developed significantly higher plasma creatinine levels and had a lower number of oxygen free days (posterior mean difference 10.57 micromol/L, 95% HPD interval 2.43 - 18.92, rate ratio 0.55- 95% HPD interval 0.31- 0.99 respectively). There were no other statistically significant differences in endpoints between Nafamostat and SoC. PK data demonstrated that intravenous Nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. Participants in the Nafamostat group had higher D-Dimers.Interpretation: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous Nafamostat. Further evaluation of Nafamostat delivered via a different route may be warranted.Clinical Trial Registration Details: This trial has been registered on ISRCTN (https://www.isrctn.com/) ISRCTN14212905, and Clinicaltrials.gov (https://www.clinicaltrials.gov/) NCT04473053. Funding Information: DEFINE was funded by LifeArc (an independent medical research charity under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).Declaration of Interests: The authors report no conflict of interests.Ethics Approval Statement: The DEFINE trial has received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian. Written informed consent was taken by trial clinicians prior to any trial procedures being performed. If a patient lacked capacity, consent could be provided by their next of kin.

DEFINE: A Phase IIa Randomised Controlled Trial to Evaluate Repurposed Treatments for COVID-19 (preprint)

IntroductionCOVID-19 (Coronavirus Disease 2019) is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS CoV2 (Severe Acute Respiratory Syndrome Coronavirus 2). At present there are few proven effective treatments. This early phase experimental medicine protocol describes an overarching and adaptive trial designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy, which may support further development and deployment of candidate therapies in larger scale trials of COVID-19 positive patients. Methods and analysisDEFINE is an ongoing exploratory multicentre platform, open label, randomised study. COVID-19 positive patients will be recruited from the following cohorts; a) community cases b) hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT) scan or requiring supplemental oxygen and c) hospitalised patients requiring assisted ventilation. Participants may be recruited from all three of these cohorts, depending on the experimental therapy, its route of administration and mechanism of action. The primary statistical analyses are concerned with the safety of candidate agents as add-on therapy to standard of care in patients with COVID-19. Safety will be assessed usingO_LIHaematological and biochemical safety laboratory investigations. C_LIO_LIPhysical examination C_LIO_LIVital signs (blood pressure/heart rate/temperature and respiratory rate) C_LIO_LIDaily electrocardiogram (ECG) readings C_LIO_LIAdverse events C_LI The analysis population will consist of (i) all patients randomised to a treatment arm who receive any dose of the study drug and (ii) all patients randomised to the control arm who would also have been eligible to receive a study drug. Secondary analysis will assess the following variables during treatment period 1) the response of key exploratory biomarkers 2) change in WHO ordinal scale and NEWS2 score 3) oxygen requirements 4) viral load 5) duration of hospital stay 6) PK/PD and 7) changes in key coagulation pathways. Ethics and disseminationThe DEFINE trial platform and its initial two treatment and standard of care arms have received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian and NHS Greater Glasgow and Clyde. The results of each study arm will be published as soon as the treatment arm has finished recruitment, data input is complete and any outstanding patient safety follow-ups have been completed. Depending on the results of these or future arms, data will be shared with larger clinical trial networks, including RECOVERY, and to other partners for rapid roll out in larger patient cohorts. Registration detailsThe DEFINE protocol has been registered on ISRCTN (https://www.isrctn.com/) and Clinicaltrials.gov(https://www.clinicaltrials.gov/). ClinicalTrials.gov Identifier: NCT04473053 ISRCTN Identifier: ISRCTN14212905 Strengths and limitations of this studyO_LIThe trial is as flexible as possible to ensure a broad range of patients can be recruited and candidate therapies can be added or removed as evidence emerges. C_LIO_LIThe team are collecting real world data of medications at an early stage of their use in COVID-19 across the full spectrum of disease; allowing the administration of different treatment formulations (inhaled vs oral vs intravenous). C_LIO_LIThe simultaneous collection of clinical outcomes as well as exploratory endpoints including clinical biomarkers, flow cytometry, PK/PD and thromboelastography allows further characterisation and elucidation of the temporal immuno-inflammatory cascade in COVID-19 to inform on future therapy selection. C_LIO_LIThis is a Phase 1b/IIa platform study and thus the primary end point is clinical safety therefore our anticipated numbers will be too small to allow for definitive data on efficacy. C_LIO_LIDEFINE is an experimental medicine platform, currently restricted to three clinical sites and so the generation of data will be slower than that of larger platforms with access to a greater number of patients. C_LI

Diagnostic performance of the combined nasal and throat swab in patients admitted to hospital with suspected COVID-19 (preprint)

Background: Accurate diagnosis in patients with suspected coronavirus disease 2019 (COVID-19) is essential to guide treatment and limit spread of the virus. The combined nasal and throat swab is used widely, but its diagnostic performance is uncertain. Methods: In a prospective, multi-centre, cohort study conducted in secondary and tertiary care hospitals in Scotland, we evaluated the combined nasal and throat swab with reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in consecutive patients admitted to hospital with suspected COVID-19. Diagnostic performance of the index and serial tests was evaluated for a primary outcome of confirmed or probable COVID-19, and a secondary outcome of confirmed COVID-19 on serial testing. The diagnosis was adjudicated by a panel, who recorded clinical, laboratory and radiological features blinded to the test results. Results: We enrolled 1,369 consecutive patients (68 [53-80] years, 47% women) who underwent a total of 3,822 tests (median 2 [1-3] tests per patient). The primary outcome occurred in 36% (496/1,369), of whom 65% (323/496) and 35% (173/496) had confirmed and probable COVID-19, respectively. The index test was positive in 255/496 (51%) patients with the primary outcome, giving a sensitivity and specificity of 51.4% (95% confidence interval [CI] 48.8 to 54.1%) and 99.5% (95% CI 99.0 to 99.8%). Sensitivity increased in those undergoing 2, 3 or 4 tests to 60.1% (95% CI 56.7 to 63.4%), 68.3% (95% CI 64.0 to 72.3%) and 77.6% (95% CI 72.7 to 81.9%), respectively. The sensitivity of the index test was 78.9% (95% CI 74.4 to 83.2%) for the secondary outcome of confirmed COVID-19 on serial testing. Conclusions: In patients admitted to hospital, a single combined nasal and throat swab with RT-PCR for SARS-CoV-2 has excellent specificity, but limited diagnostic sensitivity for COVID-19. Diagnostic performance is significantly improved by repeated testing.