ABSTRACT
Introduction/Aim: We conducted an open label, randomized, controlled trial to assess whether fluvoxamine combined with bromhexine, given during mild to moderate SARS-CoV-2 illness, prevented clinical deterioration due to their proposed immune modulatory effects. Method(s): Participants had confirmed SARS-CoV-2 infection, experiencing mild to moderate symptoms and oxygen saturation of >=92%. Participants were randomly assigned to receive fluvoxamine (100 mg days 1 and 2, followed by 150 mg daily till day 14) with bromhexine (FLU/BRO) (16 mg daily till day 10) or favipiravir alone (FAV) (3600 mg day 1 followed by 1600 mg daily till day 5). Primary outcome was clinical deterioration within 30 days of randomization defined as shortness of breath or hospitalization for shortness of breath or pneumonia and oxygen saturation >=92%, on room air or need for supplemental oxygen to achieve oxygen saturation of >=92%. Result(s): 158 participants were randomized (average age 50 years (range 18-68 years);68 [43%] women), and 142 (89%) completed the trial. 0/78 participants experience clinical deterioration with FLU/BRO and 18/64 patients with FAV. TNF-alpha, IL-6 IL-8 and IL-1beta levels were significantly (p < 0.005) reduced with FLU/BRO compared to FAV at day 3, 5, 7 and 14. 0/78 participants had long COVID symptoms with FLU/BRO compared to 32/64 (50%) with FAV (p < 0.005). One serious (clumsiness or unsteadiness) and 10 other adverse events were reported with FLU/BRO compared to 5 serious and 12 other adverse events with FAV. Conclusion(s): Results suggest there was significantly less clinical deterioration in symptomatic COVID-19 participants treated with FLU/BRO.
ABSTRACT
Background: SARS-CoV-2 variants resistant to monoclonal antibodies, and drug-drug interactions and potential mutagenicity of direct acting antivirals, heightens the need for additional therapeutics to prevent progression to severe COVID-19. Exogenous interferon beta is a promising therapeutic option against SARS-CoV-2 given its broad-spectrum antiviral activity and data suggesting impaired endogenous IFN production in individuals with severe disease. Method(s): The safety and efficacy of orally inhaled nebulized interferon-beta1a (SNG001) was evaluated in a Phase II randomized controlled trial on the ACTIV-2/ A5401 platform (NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized to SNG001 once daily for 14 days or blinded pooled placebo. Primary outcomes included treatment-emergent Grade >=3 adverse event (TEAE) through day 28;time to symptom improvement of 13 targeted COVID-19 symptoms collected by daily study diary through day 28;and SARS-CoV-2 RNA < lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs at days 3, 7, and 14. All-cause hospitalization or death through day 28 was a key secondary outcome. Result(s): Of 221 participants enrolled at 25 US sites between February and August 2021, 220 (110 SNG001, 110 placebo) initiated study intervention, with a median age of 40 years, 55% female, and 20% SARS-CoV-2 vaccinated. There was no significant difference between SNG001 and placebo in Grade >=3 TEAEs (4% vs 8%, Fisher's exact test p=0.25). Median time to symptom improvement was 13 days for SNG001 and 9 days for placebo (Gehan-Wilcoxon test p=0.17). There was no difference in the proportion of participants with SARS-CoV-2 RNA < LLoQ at day 3, 7 or 14 (SNG001 vs placebo, Day 3: 28% vs. 39%;Day 7: 65% vs. 66%;Day 10: 91% vs. 91%;joint Wald test p=0.41). There were fewer hospitalizations with SNG001 (n=1;1%) compared with placebo (n=7;6%), but this difference was not statistically significant (Fisher's exact test p=0.07;Figure). All hospitalizations were due to COVID-19 and occurred among unvaccinated participants without protocol-defined high-risk factors. Conclusion(s): Inhaled nebulized SNG001 was safe and well tolerated but did not reduce SARS-CoV-2 RNA levels in the nasopharynx nor decrease time to improvement of COVID-19 symptoms in outpatients with mild-to-moderate COVID-19. The non-statistically significant decrease in hospitalizations among SNG001 participants warrants further investigation in a phase 3 clinical trial. Cumulative incidence of hospitalization or death comparing SNG001 vs. placebo.
ABSTRACT
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.
ABSTRACT
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).
ABSTRACT
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).