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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

Our take —

In this multicenter, phase 2, double-blinded randomized controlled trial, treatment with nebulized interferon beta-1a (SNG001) showed good tolerability, increased odds of clinical status improvement by OSCI score, and increased chances of clinical recovery during the treatment period as compared to placebo. Small sample size, loss to follow-up, and imbalances at randomization may limit generalizability of study findings. In addition, the key findings require validation in other randomized controlled trials.

Study design

Randomized Controlled Trial

Study population and setting

101 patients with COVID-19 were randomized 1:1 to inhaled nebulized interferon beta-1a (SNG001) or placebo at nine UK centers. A total of 48 patients received SNG001 and 50 received placebo, leading to a total of 98 patients included in the intention-to-treat analysis (ITT); 75 participants were treated per protocol (PP – 39 receiving SNG001 and 36 receiving placebo). Treatments were administered by inhalation via a mouthpiece once daily for 14 days. Patients included in this study were adults admitted to hospital with COVID-19 symptoms, within 24 hours of demonstrated evidence of infection by positive RT-PCR and/or point-of-care test. Information on clinical presentation and scoring on the WHO Ordinal Scale for Clinical Improvement (OSCI) and the Breathlessness, Cough And Sputum Scale (BCSS) were collected at the start of the study and then twice daily. Follow-up occurred for up to 28 days. The primary outcome was variation in clinical condition based on the OSCI scale.

Summary of Main Findings

Mean age was 57.1 years, 59% were male, and 80% were White. Intervention and control groups were dissimilar at baseline in a number of categories, including disease severity measured by the OSCI score (need for oxygen supplementation occurred in 77% in the SNG001 group vs. 58% in the placebo group), prevalence of diabetes (33% in SNG001 vs. 12% in placebo), cardiovascular disease (30% in SNG001 vs. 19% in placebo), and hypertension (41% in SNG001 vs. 69% in placebo). Median duration of symptoms at time of intervention was 10 days. Patients in the SNG001 were at greater odds of OSCI scale clinical improvement on days 15 and 16 (OR 2.32 [95% CI 1.07–5.04]; p=0·033), and on day 28 (3.15 [95% CI 1.39–7.14]; p 0.006) after treatment initiation, as compared to placebo; results were similar whether in ITT or PP analyses. Likelihood of recovering to an OSCI score of 1 during the treatment period was higher among patients receiving SNG001 (hazard ratio HR 2.19 [95% CI 1.03–4.69]; p 0.043). Headache was the most frequent treatment-emergent adverse event, and occurred in 15% of patients in the SNG001 group and 10% in the placebo group. There were three deaths in the placebo group and none in the SNG001 group. Serious adverse events, including pneumonia and respiratory failure, were seen in 15% of SNG001 patients and 28% of placebo. Those were considered unlikely to be related to the study treatment

Study Strengths

This was a double-blinded, multi-center, randomized controlled trial of an antiviral against SARS-CoV-2. Primary and secondary outcomes included safety, tolerability, and changes in clinical condition. The duration of symptoms at baseline is increasingly recognized as a key determinant in whether an antiviral might be effective: in the present study the duration of symptoms at baseline was well-balanced between the groups receiving SNG001 and placebo, and was under 14 days in most participants.

Limitations

This was a pilot study with a small sample size. The proportion of participants who did not complete 28 day follow up was 23% (14 receiving SNG001 and 9 receiving placebo): this appears to be somewhat high. Findings might not be generalizable and must be explored in larger phase 2 trials and subsequent phase 3 trials. In addition, the study population did not include patients with mild symptoms with no need for hospitalization, or patients under mechanical ventilation. Furthermore, the groups were imbalanced at baseline with respect to several key risk factors for COVID-19, although generally these factors would have favored bias against SNG001. Importantly, BMI was not explicitly addressed as a participant characteristic, nor as a factor used in multi-variable adjustment, although a wealth of evidence has shown that BMI is a risk factor for COVID-19 disease severity. In addition, fewer participants in the placebo group had higher oxygen needs at baseline (56%) compared to participants in the SNG001 group (75%), which might cause regression to the mean during the natural course of disease.

Value added

This was a multicentric randomized controlled trial of 98 patients hospitalized with COVID-19 that showed good tolerance of SNG001 and efficacy in improving odds of clinical status improvement and recovery as compared to placebo. If validated in larger studies, the 79% reduction in odds of severe disease or death conferred by SNG001 compared to placebo is among the largest benefits observed for a pharmacologic agent in a double-blinded RCT of COVID-19.

This review was posted on: 20 November 2020