Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-blind, randomised, placebo-controlled, phase 3 trial

Abstract

Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs plac...

Whole-genome sequencing reveals host factors underlying critical COVID-19

“…Although our genome-wide gene-based association tests did not replicate any findings from a previous pathway-specific study of rare deleterious variants 4 , our results provide robust evidence implicating reduced interferon signalling in susceptibility to critical Covid-19. Importantly, systemic administration of interferon in two large clinical trials, albeit late in disease, did not reduce mortality 31,32 .…”

Impact of early interferon-β treatment on the prognosis of patients with COVID-19 in the first wave: A post hoc analysis from a multicenter cohort

“…Both groups were similar, but contrary to our study, only 6.7% (INF-β) and 6.3% (control) of patients were on ventilation support, and only 33.7% and 34.7% were hospitalized ≥ 2 days. Similarly, a multicenter randomized controlled trial by Kalil et al did not show efficacy of INF-β combined with remdesivir compared to remdesivir alone concerning time to recovery [14] . Patients had mostly mild-to-moderate COVID-19, with only 7% in both groups requiring non-invasive ventilation or high-flow oxygen therapy.…”

“…Promising results obtained from three randomized controlled trials with small sample sizes showed that subcutaneous injection of IFN-β in patients with moderate-to-severe COVID-19 improved clinical outcomes with no specific side effects [10] , [11] , [12] . However, two other multicenter randomized controlled trials, mostly in adult inpatients with mild-to-moderate COVID-19, did not show clinical efficacy of interferon treatment [13] , [14] .…”

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections

“…In addition, earlier intramuscular administration of IFN-α was suggested to be beneficial for COVID-19 patients (10.2217/fvl-2020-0404). Moreover, differences in biological activity and structure between different type I IFNs may reduce the transcription of ISGs, and eliminate the synergistic effect of the combinational treatment [71]. Therefore, the overall antiviral effect for treatment with IFNs in vivo could be dampened.…”