PROphylaxis for paTiEnts at risk of COVID-19 infecTion (PROTECT-V).

BACKGROUND: Despite the introduction of vaccination, there remains a need for pre-exposure prophylactic agents against SARS-CoV-2. Several patient groups are more vulnerable to SARS-CoV-2 infection by virtue of underlying health conditions, treatments received or suboptimal responses to vaccination. METHODS: PROTECT-V is a platform trial testing pre-exposure prophylactic interventions against SARS-CoV-2 infection in vulnerable patient populations (organ transplant recipients; individuals with oncological/haematological diagnoses, immune deficiency or autoimmune diseases requiring immunosuppression or on dialysis). Multiple agents can be evaluated across multiple vulnerable populations sharing placebo groups, with the option of adding additional treatments at later time points as these become available. The primary endpoint is symptomatic SARS-CoV-2 infection, and each agent will be independently evaluated in real time when the required number of events occurs. Presently, three agents are approved in the platform: intranasal niclosamide, nasal and inhaled ciclesonide and intravenous sotrovimab. DISCUSSION: Despite the introduction of vaccination, there remains a need for pre-exposure prophylactic agents against SARS-CoV-2. Several patient groups are more vulnerable to COVID-19 disease by virtue of underlying health conditions, treatments received or suboptimal responses to vaccination. TRIAL REGISTRATION: ClinicalTrials.gov NCT04870333. EudraCT 2020-004144-28.

Nebulised interferon-ß1a (SNG001) in hospitalised COVID-19: SPRINTER phase III study.

Background: Despite the availability of vaccines and therapies, patients are being hospitalised with coronavirus disease 2019 (COVID-19). Interferon (IFN)-ß is a naturally occurring protein that stimulates host immune responses against most viruses, including severe acute respiratory syndrome coronavirus 2. SNG001 is a recombinant IFN-ß1a formulation delivered to the lungs via nebuliser. SPRINTER assessed the efficacy and safety of SNG001 in adults hospitalised due to COVID-19 who required oxygen via nasal prongs or mask. Methods: Patients were randomised double-blind to SNG001 (n=309) or placebo (n=314) once daily for 14 days plus standard of care (SoC). The primary objective was to evaluate recovery after administration of SNG001 versus placebo, in terms of times to hospital discharge and recovery to no limitation of activity. Key secondary end-points were progression to severe disease or death, progression to intubation or death and death. Results: Median time to hospital discharge was 7.0 and 8.0 days with SNG001 and placebo, respectively (hazard ratio (HR) 1.06 (95% CI 0.89-1.27); p=0.51); time to recovery was 25.0 days in both groups (HR 1.02 (95% CI 0.81-1.28); p=0.89). There were no significant SNG001-placebo differences for the key secondary end-points, with a 25.7% relative risk reduction in progression to severe disease or death (10.7% and 14.4%, respectively; OR 0.71 (95% CI 0.44-1.15); p=0.161). Serious adverse events were reported by 12.6% and 18.2% patients with SNG001 and placebo, respectively. Conclusions: Although the primary objective of the study was not met, SNG001 had a favourable safety profile, and the key secondary end-points analysis suggested that SNG001 may have prevented progression to severe disease.

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial.

BACKGROUND: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. METHODS: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. FINDINGS: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. INTERPRETATION: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19. FUNDING: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.

Nebulised interferon beta-1a (SNG001) in hospitalised COVID-19: SPRINTER Phase III Study

Background Despite the availability of vaccines and therapies, patients are being hospitalised with COVID-19. Interferon-β is a naturally-occurring protein that stimulates host immune responses against most viruses, including SARS-CoV-2. SNG001 is a recombinant interferon-β1a formulation delivered to the lungs via nebuliser. SPRINTER assessed the efficacy and safety of SNG001 in adults hospitalised due to COVID-19 who required oxygen via nasal prongs or mask. Methods Patients were randomised double-blind to SNG001 (N=309) or placebo (N=314) once-daily for 14 days plus standard of care (SoC). The primary objective was to evaluate recovery after administration of SNG001 versus placebo, in terms of times to hospital discharge and recovery to no limitation of activity. Key secondary endpoints were: progression to severe disease or death;progression to intubation or death;and death. Results Median time to hospital discharge was 7.0 and 8.0 days with SNG001 and placebo, respectively (hazard ratio 1.06 [95%CI 0.89, 1.27];p=0.51);time to recovery was 25.0 days in both groups (1.02 [0.81, 1.28];p=0.89). There were no significant SNG001–placebo differences for the key secondary endpoints, with a 25.7% relative risk reduction in progression to severe disease or death (10.7% and 14.4%, respectively;odds ratio 0.71 [0.44, 1.15];p=0.161). Serious adverse events were reported by 12.6% and 18.2% patients with SNG001 and placebo, respectively. Conclusions Although the primary objective of the study was not met, SNG001 had a favourable safety profile, and the key secondary endpoints analysis suggested that SNG001 may have prevented progression to severe disease. Study registration number: ISRCTN85436698

Coronary artery thrombus resulting in ST-elevation myocardial infarction in a patient with COVID-19.

COVID-19 is a prothrombotic condition that is also associated with raised troponin levels and myocardial damage. We present a case of a 54-year-old man who was admitted with respiratory failure due to COVID-19 and developed a ST-elevation myocardial infarction (STEMI) during his admission. His coronary angiogram did not show any significant coronary artery disease other than a heavily thrombosed right coronary artery. In view of heavy thrombus burden, the right coronary artery was treated with thrombus retrieval using a distal embolic protection device in addition to manual thrombectomy and direct (intracoronary) thrombolysis without the need for implantation of a coronary stent. After successful revascularisation, triple antithrombotic therapy was instituted with an oral anticoagulant in addition to dual antiplatelets. This case illustrates the association of COVID-19 with coronary artery thrombosis, which may require disparate management of a STEMI than that resulting from atherosclerotic coronary artery disease.

COVID-19 admission risk tools should include multiethnic age structures, multimorbidity and deprivation metrics for air pollution, household overcrowding, housing quality and adult skills.

BACKGROUND: Ethnic minorities account for 34% of critically ill patients with COVID-19 despite constituting 14% of the UK population. Internationally, researchers have called for studies to understand deterioration risk factors to inform clinical risk tool development. METHODS: Multicentre cohort study of hospitalised patients with COVID-19 (n=3671) exploring determinants of health, including Index of Multiple Deprivation (IMD) subdomains, as risk factors for presentation, deterioration and mortality by ethnicity. Receiver operator characteristics were plotted for CURB65 and ISARIC4C by ethnicity and area under the curve (AUC) calculated. RESULTS: Ethnic minorities were hospitalised with higher Charlson Comorbidity Scores than age, sex and deprivation matched controls and from the most deprived quintile of at least one IMD subdomain: indoor living environment (LE), outdoor LE, adult skills, wider barriers to housing and services. Admission from the most deprived quintile of these deprivation forms was associated with multilobar pneumonia on presentation and ICU admission. AUC did not exceed 0.7 for CURB65 or ISARIC4C among any ethnicity except ISARIC4C among Indian patients (0.83, 95% CI 0.73 to 0.93). Ethnic minorities presenting with pneumonia and low CURB65 (0-1) had higher mortality than White patients (22.6% vs 9.4%; p<0.001); Africans were at highest risk (38.5%; p=0.006), followed by Caribbean (26.7%; p=0.008), Indian (23.1%; p=0.007) and Pakistani (21.2%; p=0.004). CONCLUSIONS: Ethnic minorities exhibit higher multimorbidity despite younger age structures and disproportionate exposure to unscored risk factors including obesity and deprivation. Household overcrowding, air pollution, housing quality and adult skills deprivation are associated with multilobar pneumonia on presentation and ICU admission which are mortality risk factors. Risk tools need to reflect risks predominantly affecting ethnic minorities.

Increase in recruitment upon integration of trial into a clinical care pathway: an observational study.

INTRODUCTION: Many respiratory clinical trials fail to reach their recruitment target and this problem exacerbates existing funding issues. Integration of the clinical trial recruitment process into a clinical care pathway (CCP) may represent an effective way to significantly increase recruitment numbers. METHODS: A respiratory support unit and a CCP for escalation of patients with severe COVID-19 were established on 11 January 2021. The recruitment process for the Randomised Evaluation of COVID-19 Therapy-Respiratory Support trial was integrated into the CCP on the same date. Recruitment data for the trial were collected before and after integration into the CCP. RESULTS: On integration of the recruitment process into a CCP, there was a significant increase in recruitment numbers. Fifty patients were recruited over 266 days before this process occurred whereas 108 patients were recruited over 49 days after this process. There was a statistically significant increase in both the proportion of recruited patients relative to the number of COVID-19 hospital admissions (change from 2.8% to 9.1%, p<0.0001) and intensive therapy unit admissions (change from 17.8% to 50.2%, p<0.001) over the same period, showing that this increase in recruitment was independent of COVID-19 prevalence. DISCUSSION: Integrating the trial recruitment process into a CCP can significantly boost recruitment numbers. This represents an innovative model that can be used to maximise recruitment without impacting on the financial and labour costs associated with the running of a respiratory clinical trial.

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established.Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population.Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death.Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71).Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.