Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial

Abstract

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection carries a substantial risk of severe and prolonged illness; treatment options are currently limited. We assessed the efficacy and safety of inhaled nebulised interferon beta-1a (SNG001) for the treatment of patients admitted to hospital with COVID-19. Methods We did a randomised, double-blind, placebo-controlled, phase 2 pilot trial at nine UK sites. Adults aged 18 years or older and admitted to hospital with COVID-19 symptoms, with a positive RT-PCR or point-of-care test, or both, were randomly assigned (1:1) to receive SNG001 (6 MIU) or placebo by inhalation via a mouthpiece daily for 14 days. The primary outcome was the change in clinical condition on the WHO Ordinal Scale for Clinical Improvement (OSCI) during the dosing period in the intention-to-treat population (all randomised patients who received at least one dose of the study drug). The OSCI is a 9-point scale, where 0 corresponds to no infection and 8 corresponds to death. Multiple analyses were done to identify the most suitable statistical method for future clinical trials. Safety was assessed by monitoring adverse events for 28 days. This trial is registered with Clinicaltrialsregister.eu (2020-001023-14) and ClinicalTrials.gov ( NCT04385095 ); the pilot trial of inpatients with COVID-19 is now completed. Findings Between March 30 and May 30, 2020, 101 patients were randomly assigned to SNG001 (n=50) or placebo (n=51). 48 received SNG001 and 50 received placebo and were included in the intention-to-treat population. 66 (67%) patients required oxygen supplementation at baseline: 29 in the placebo group and 37 in the SNG001 group. Patients receiving SNG001 had greater odds of improvement on the OSCI scale (odds ratio 2·32 [95% CI 1·07–5·04]; p=0·033) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (hazard ratio 2·19 [95% CI 1·03–4·69]; p=0·043). SNG001 was well tolerated. The most frequently reported treatment-emergent adverse event was headache (seven [15%] patients in the SNG001 group and five [10%] in the placebo group). There were three deaths in the placebo group and none in the SNG001 group. Interpretation Patients who received SNG001 had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo, providing a strong rationale for further trials. Funding Synairgen Research.

Nebulised interferon beta-1a for patients with COVID-19

“… 5 However, preliminary results from the SOLIDARITY/DisCoVeRy randomised clinical trial in more than 2000 patients showed no efficacy of subcutaneous interferon alone or with lopinavir–ritonavir. 6 The results of the present pilot study, 1 in contrast to the results of the SOLIDARITY trial, corroborate findings from in-vitro studies and animal models showing that the interferon pathway is crucial in controlling SARS-CoV-2 infection.…”

“…First, the population targeted by these studies was different. The population in the present pilot study 1 was overall at a less severe stage of COVID-19 than that in the SOLIDARITY trial; no patients with invasive ventilation were included, whereas 8% of patients in SOLIDARITY were ventilated; and global mortality was 3% at 28 days in the present study versus 12% in SOLIDARITY. Second, the route of administration of interferon beta-1a was different in these studies: the present study used nebulised therapy that delivers interferon beta-1a directly to the respiratory tract, whereas the SOLIDARITY trial used subcutaneous interferon beta-1a.…”

“…In The Lancet Respiratory Medicine , Phillip Monk and colleagues 1 report the results of a randomised, double-blind, placebo-controlled phase 2 pilot trial of nebulised interferon beta-1a in 101 adults admitted to hospital with COVID-19. The authors found that patients who received nebulised interferon beta-1a had significantly greater odds of clinical improvement across the WHO Ordinal Scale for Clinical Improvement than those who received placebo, both on day 15/16 (odds ratio [OR] 2·32 [95% CI 1·07–5·04]; p=0·033) and on day 28 (3·15 [1·39–7·14]; p=0·006).…”

A review of potential suggested drugs for coronavirus disease (COVID-19) treatment

“…Headache was more commonly experienced by patients in the interferon and placebo group. The mortality report belonged to the placebo group (three patients) ( Monk et al, 2020 ). A randomized open-label, Phase 2 trial enrolled 127 COVID-19 related hospitalized patients to treat a combination antiviral regimen or lopinavir/ritonavir as a control.…”

The Need for Antiviral Drugs for Pandemic Coronaviruses From a Global Health Perspective

“…In RCTs that evaluated earlier time points, favipiravir plus interferon-α reported clinical improvement in subjects with symptoms ≤7 days, and in a randomized open-label trial of lopinavir-ritonavir, interferon beta-1b, and ribavirin compared to lopinavir-ritonavir alone, post-hoc subgroup analysis showed a shorter time to negative PCR and clinical improvement in subjects treated within 7 days of symptom onset, but no benefit if treated later (31,32). Subsequent trials of interferon have shown mixed results (30,33,34). More recently, monoclonal antibodies targeting the SARS-CoV-2 spike protein are reported to possibly reduce hospitalizations when given within a median of 4 days of symptoms, whereas, monoclonal antibody therapy was not effective in hospitalized patients (35).…”