SPRINTER: A Randomized, Double-Blind, Placebo Controlled, Phase 3 Trial to Determine the Efficacy and Safety of Inhaled Interferon Beta-1a (SNG001)for the Treatment of Patients Hospitalised Due to COVID-19 (NCT04732949)

Rationale: Interferon beta (IFN-beta) is key in host defence against viruses but can be suppressed by virus or host factors locally at the site of infection. Inhalation of SNG001 (IFN-beta-1a nebuliser solution) aims to restore lung IFN-beta levels. Method(s): Adults hospitalised due to COVID-19 requiring low flow oxygen were randomized to receive SNG001 (314) or placebo (309) OD for 14 days, plus standard-of-care. Efficacy was assessed by change in clinical condition using the WHO 9-point Ordinal Scale for Clinical Improvement (OSCI). Primary endpoints: time to discharge (OSCI <=2) and time to recovery (OSCI <=1). Key secondary endpoints: progression to severe disease or death (OSCI >=5), progression to intubation or death (OSCI >=6), and death. Result(s): Most patients were discharged rapidly from hospital and there was no effect of SNG001 on time to discharge or recovery. However, there was an encouraging signal for prevention of progression to severe disease or death (ITT 26% relative risk reduction (RRR);Odds Ratio (95% CI): 0.71 (0.44, 1.15);Per Protocol 36% RRR;OR 0.63 (0.35, 1.13)). Post hoc analyses supported this observation with enhanced effects favouring SNG001 in subgroups at higher risk of progression (>=65 years;>=1 comorbidity;oxygen saturation <=92% and/or respiratory rate >=21 breaths/min on oxygen). Conclusion(s): If the encouraging signal in the relative risk of disease progression or death (~30% reduction) observed in this 300 patient/arm trial were confirmed in a larger trial, SNG001 could become a useful treatment option for hospitalised COVID-19 patients.

Dipeptidyl Peptidase-1 Inhibition in Patients Hospitalized with COVID-19: a Multicentre Randomized Double-Blind Placebo Controlled Trial

Background: Neutrophil serine proteases (NSPs) are involved in the pathogenesis of COVID19 and are increased in severe and fatal infection. We investigated whether treatment with Brensocatib, an inhibitor of dipeptidyl peptidase-1, an enzyme responsible for the activation of NSPs, would improve outcomes in hospitalized patients with COVID19. Method(s): In a randomized, double-blind, placebo-controlled trial, 406 hospitalized patients with COVID19 with at least one risk factor for severe disease were randomized 1:1 to once-daily Brensocatib 25mg (n=192) or placebo (n=214) for 28 days. Primary outcome was the 7-point World Health Organisation Clinical Status scale at day 29. Secondary outcomes included time to clinical improvement, national early warning score, new oxygen and ventilation use, neutrophil elastase activity in blood and mortality. Finding(s): Brensocatib treatment was associated with worse clinical status at day 29 (adjusted odds ratio 0 72, 95%CI 0 57-0 92) compared to placebo. The adjusted hazard ratio (aHR) for time to clinical improvement was 0 87 (95%CI 0 76-1 00) and time to hospital discharge was 0 98 (95%CI 0 84-1 13). During the 28-day follow-up period, 23 (11%) and 29 (15%) patients died in the placebo and Brensocatib treated groups respectively). Oxygen and new ventilation use were greater in the Brensocatib treated patients. Neutrophil elastase activity in blood was significantly reduced in the Brensocatib group from baseline to day 29. Prespecified subgroup analyses of the primary outcome supported the primary results.

Inflammation profiling and recovery clusters five months post-hospitalisation for COVID-19

Background Understanding the underlying mechanisms of post-COVID sequelae (Long COVID) is urgently needed to guide interventions. Aim To compare the inflammation profiles of four recovery clusters post-hospitalisation. Methods Post-Hospitalisation COVID-19 (PHOSP-COVID) is a prospective, multi-centre study across UK. Four recovery clusters previously identified using clinical data (symptoms, mental health, cognitive impairment, and physical function) at 5 months post-discharge were used based on severity of on-going health impairments: very severe, severe, moderate (cognitive), and mild. Inflammatory profiling performed from plasma samples using the Olink Explore 384 inflammation panel. Multinomial logistic regression for each protein was undertaken comparing the mild cluster with each of the remaining clusters with FDR of 0.1 to adjust p values. Results 626 participants (clusters: very severe n=111, severe n=173, moderate/cognitive n=73 and mild n=269). Proteomic results from 296 proteins were included. After adjustment for age, BMI, and comorbidity count, 13 proteins were significantly elevated in the very severe cluster, and 2 proteins in the moderate/cognitive cluster, compared to the mild cluster (Figure 1). Conclusion Inflammatory mediators consistent with persistent lung and systemic inflammation were associated with the severity of ongoing health impairments highlighting potential therapeutic pathways to be tested.

Characteristics and risk factors for persistent breathlessness after hospitalisation for COVID-19

Background: Persisting breathlessness after COVID-19 infection is common and debilitating. We aimed to characterise and identify risk factors for patients with persistent breathlessness following COVID-19 hospitalisation. Method(s): PHOSP-COVID is a multi-centre prospective cohort study of UK adults hospitalised for COVID-19. Clinical data were collected during hospitalisation and at a research visit. Breathlessness was measured by a numeric rating scale of 0-10. We defined post-COVID breathlessness as an increase in score of 1 or more compared to the preCOVID-19 level. Multivariable logistic regression was used to identify risk factors. Result(s): We included 1,226 participants (37% female, median age 59 years, 22% mechanically ventilated). At a median five months after discharge, 50% reported post-COVID breathlessness. Risk factors for post-COVID breathlessness were socio-economic deprivation (adjusted odds ratio, 1.67;95% confidence interval, 1.14-2.44), pre-existing depression/anxiety (1.58;1.06-2.35), female sex (1.56;1.21-2.00) and admission duration (1.01;1.00- 1.02). Black ethnicity (0.56;0.35-0.89) and older age groups (0.31;0.14-0.66) were less likely to report post-COVID breathlessness. Post-COVID breathlessness was associated with worse performance on the shuttle walk test and forced vital capacity, but not with obstructive airflow limitation. Conclusion(s): Half of this national cohort of patients hospitalised for COVID-19 experienced persistent breathlessness at follow up. The risk factors identified for post-COVID breathlessness should inform mechanistic work to understand causal processes and develop future interventions to improve outcomes in this growing population.

Impact of Treatment of Hospitalised COVID-19 Patients With Inhaled Interferon Beta-1a (SNG001) on Long COVID Symptoms: Results From the SPRINTER trial

Background. People with post-COVID conditions can have a wide range of symptoms lasting months and it can affect as many as one in five infected people. Interferon beta (IFN-beta) is key in host defence against viruses but can be suppressed by virus or host factors locally at the site of infection. Inhalation of SNG001 (IFN-beta-1a nebuliser solution) aims to restore lung IFN-beta levels. SPRINTER (NCT04732949) was a RCT of inhaled interferon beta in hospitalised COVID-19. There was no effect of SNG001 on the primary endpoints of time to discharge or recovery most likely due to improvements in the standard of care. However, there was an encouraging signal for the key secondary endpoint of prevention of progression to severe disease or death (ITT 26% relative risk reduction [RRR];Odds Ratio [95% CI]: 0.71 [0.44, 1.15];Per Protocol 36% RRR;OR 0.63 [0.35, 1.13]). Post hoc analyses showed enhanced effects favouring SNG001 in subgroups at higher risk of progression. We report on the impact of SNG001 on long COVID symptoms in SPRINTER. Methods. Patients requiring low-flow oxygen were randomized to receive SNG001 (314) or placebo (309) once daily for 14 days, plus standard-of-care. Long COVID symptoms were assessed as a secondary endpoint at follow-up visits via telephone/ video call on Day 60 and Day 90. The following patient reported outcome (PRO) measures were also assessed: General Anxiety Disorder 7 Questionnaire (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale and Brief Pain Inventory (Short Form). Results. When compared to placebo, SNG001 reduced the relative risk of common symptoms of long COVID (fatigue/malaise [RRR=35.4%];dyspnoea [RRR=28.3%];loss of smell and/or taste [RRR=61.4%]). Analysis of the PROs is ongoing. Conclusion. Long COVID can leave patients with lingering cognitive, respiratory, and functional symptoms months after a SARS-CoV-2 infection. Given the shift from pandemic to endemic status for COVID-19 and the need for new treatments then these findings, suggesting SNG001 may be impacting common long COVID symptoms, provide additional support for the further investigation of SNG001. (Figure Presented).

SPRINTER: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Determine the Efficacy and Safety of Inhaled Interferon Beta-1a (SNG001) for the Treatment of Patients Hospitalized Due to COVID-19 (NCT04732949)

Rationale: New effective treatments are urgently needed for patients hospitalized with COVID-19, due to lower respiratory tract illness caused by the SARS-CoV-2 virus. SARS-CoV-2 suppresses production of interferon-beta (IFN-β), a naturally occurring protein and key driver of innate antiviral immunity, to evade host immune responses. Patients with severe disease have reduced ability to generate a primary interferon response in the lungs because of genetic, comorbid and/or autoantibody host responses. In vitro, IFN-β has potent antiviral activity against SARS-CoV-2, including known variants of concern. SNG001 is an IFN-β-1a nebulizer solution administered directly into the lungs to boost IFN-β levels at the site of infection. In trials of patients with chronic respiratory diseases and viral infections, SNG001 was well tolerated and improved lung function, providing the rationale to treat patients with COVID-19, at risk of progressing to severe disease. In a phase 2 trial, non-ventilated hospitalized patients with COVID-19 receiving SNG001 were more than twice as likely to recover to “no limitation of activities” and experienced significantly reduced breathlessness over the treatment period versus those receiving placebo. These encouraging results with inhaled IFN-β supported progression of SNG001 into a phase 3 trial in patients hospitalized due to COVID-19 (SPRINTER). Methods: Adults (≥18 years) hospitalized with COVID-19, requiring supplemental oxygen via nasal prongs or mask were randomized to receive SNG001 or placebo (1:1) by inhalation once daily for 14 days, in addition to standard-of-care treatment. Efficacy was assessed in the intention-to-treat population by change in clinical condition using the WHO 9-point Ordinal Scale for Clinical Improvement (OSCI;Table). Primary endpoints: time to hospital discharge (OSCI ≤2) and time to recovery to “no limitation of activities” (OSCI ≤1). Key secondary endpoints: progression to severe disease or death (OSCI ≥5), progression to intubation or death (OSCI ≥6), and death. Cox proportional hazards modeling was used to evaluate primary endpoints. Key secondary endpoints were analyzed using logistic regression. Results: Between January and November 2021, 623 patients were randomized to treatment. Preliminary, blinded data show that median duration of symptoms was 9 days;22% (135/623) of patients were partially/fully vaccinated;median duration of hospital stay was 7 days;84% (525/623) of patients were discharged by Day 35;13% (80/623) progressed to severe disease or died within 35 days;and 5% (31/623) died within 35 days. Conclusions: Recruitment into the SPRINTER trial was completed in November 2021. Unblinded efficacy and safety results (expected Q1 2022) will be presented. (Table Presented).

Extended cohort for e-health, environment and DNA (exceed) COVID-19 focus

Background: New data collection in established longitudinal population studies provides an opportunity for studying the risk factors and sequelae of the novel coronavirus disease 2019 (COVID-19), plus the indirect impacts of the COVID-19 pandemic on wellbeing. The Extended Cohort for E-health, Environment and DNA (EXCEED) cohort is a population-based cohort (N>11,000), recruited from 2013 in Leicester, Leicestershire and Rutland. EXCEED includes consent for electronic healthcare record (EHR) linkage, spirometry, genomic data, and questionnaire data.

Prognostic value of the initial chest computerised tomography scan at one year following infection in an ethnically diverse cohort of patients admitted to hospital for COVID-19

P130 Figure 1Features of COVID-19 on the CT were very common in hospitalised patients and were related to all-cause mortality one year following hospitalisation[Figure omitted. See PDF]ConclusionEvidence of COVID-19 pneumonia on CTT is more common and severe in patients from ethnic minority groups and is independently associated with worse prognosis following hospitalisation.

Diagnosis of COVID-19 by exhaled breath analysis using gas chromatography mass spectrometry

Background: A novel human coronavirus, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), emerged in China in late 2019 and has since claimed more than one million lives. COVID-19 infection is perceived to be seasonally recurrent and a rapid non-invasive biomarker to accurately diagnose patients early-on in their disease course will be necessary to meet the operational demands for COVID-19 control in the coming years.Objective: To evaluate the role of exhaled breath volatile breath biomarkers in identifying patients with suspected or confirmed COVID 19 infection, based on their underlying reverse transcriptase polymerase chain reaction (RT-PCR) status. Methods: We conducted an observational study at Glenfield Hospital, Leicester, United Kingdom, recruiting adult patients with suspected or confirmed COVID19 pneumonia. Breath samples were collected using a standard breath collection bag, modified with appropriate filters to comply with local infection control recommendations and samples were analysed using gas chromatography mass spectrometry (GC-MS).Findings: 81 patients were recruited, of whom 52/81 (64%) have subsequently tested positive for COVID19. A LASSO regression analysis, with the dependent variable as PCR status was run. A set of seven features were extracted that had non-zero regression coefficients in at least 70 out of 100 runs of 10-fold cross validation. Compound identities were confirmed using the Metabolomics Standards Initiative (MSI). These were benzaldehyde, 1-propanol (MSI level 1), 3,6-methylundecane (MSI level 2), camphene and beta-cubebene (MSI level 1 and 2 respectively). Iodobenzene was also extracted, likely of exogenous origin, and an unidentified compound. A logistic regression model was fitted with the dependent variable as PCR status and independent variables as the seven features selected by the LASSO model. Partial Least Squares Discriminant Analysis (PLSDA) and Principal Component Analysis (PCA) were applied to the seven features, with the dependent variable as PCR status. The AUC for the first discriminant function score was 0.836 (95% CI: 0.745-0.928), Sensitivity was 0.68 (95% CI 0.551-0.809), Specificity was 0.857 (95% CI 0.728-0.987), positive predictive value (PPV) was 0.895 (95% CI 0.797-0.992) and negative predictive value (NPV) was 0.6 (95% CI 0.448-0.752). The AUC for the first PCA was 0.799 (95% CI: 0.698-0.900), Sensitivity was 0.7 (95% CI 0.573-0.827), Specificity was 0.786 (95% CI 0.634-0.938), PPV was 0.854 (95% CI 0.745-0.962) and NPV was 0.595 (95% CI 0.436-0.753).Conclusions: breath analysis has promising combined sensitivity and specificity in detecting COVID19, raising the possibility of mass rapid testing, pending external validation of the identified biomarkers.