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Interferon worse than placebo in severe COVID — US NIAID trial

Interferon beta-1a plus remdesivir (Veklury) was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen had worse outcomes with interferon compared with placebo.

In the US National Institute of Allergy and Infectious Diseases phase III ACTT-3 trial, patients in both groups had a mean five days to recovery (RR 0.99, 95% CI 0.88-1.13), and there was no significant difference in mortality rates either (5% for interferon group vs 3% for remdesivir alone, HR 1.33, 95% CI 0.69-2.55), reported Dr Andre Kalil of the University of Nebraska Medical Center in Omaha, and colleagues, writing in Lancet Respiratory Medicine.

While prior research found that interferon might improve COVID-19 outcomes, the drug showed no survival benefit in the WHO SOLIDARITY trial. Also, the NIH COVID-19 guidelines recommend against its use for patients with severe COVID, outside a clinical trial.

This stage of the Adaptive COVID-19 Treatment Trial involved 63 sites globally, 56 of them in the US. Participants were adults with laboratory-confirmed COVID-19, who had radiographic infiltrates on imaging, an oxygen saturation on room air of 94% or less, or needed supplemental oxygen. They were randomised 1[1 to receive remdesivir for up to 10 days, and up to four doses of either subcutaneous interferon beta-1a or placebo every other day.

From 5 August until 11 November 2020, 487 patients were randomised to the intervention and 452 to the control group, though the authors noted that after 4 September, the trial no longer accepted patients with ordinal scores of 6. Of the 452 patients, 448 had an ordinal score of 4 or 5, and 35 had an ordinal score of 6 at baseline due to Data Safety and Monitoring Board concerns about an increase in severe adverse events for this group.

Mean age was about 59; 58% were men and 60% were white. Nearly all patients in both groups had at least one comorbidity at baseline (89%-90%). Median duration of illness was about nine days in both groups.

There was no difference in time to improvement by 1-2 points on the ordinal scale, time to discharge, or number of days requiring supplemental oxygen, the authors noted. In addition, they said there was no difference between groups in the proportion of patients needing mechanical ventilation among patients with an ordinal scale of 4 or 5 at baseline.

Twenty-one patients in the intervention group and 16 in the controls died during the 28-day follow-up. Kaplan-Meier estimates of mortality post-28 days randomisation were 5% (95% CI 3-7) in the interferon beta-1a plus remdesivir group and 3% (95% CI 2-6) in the placebo plus remdesivir group, according to the authors. The most common grade 3 or 4 adverse event in both groups was decreased lymphocyte count (7% each).

Kalil's group hypothesised about why the ACTT-3 results might be different compared to the previous trials. They wrote that “the mechanism of interferon is to decrease viral replication”, but since it was administered with antiviral remdesivir, there may not have been “additional antiviral effects”, they noted. Trial designs were also different, with prior trials enrolling patients with milder illness.

Nevertheless, they considered their results definitive when comparing them to smaller studies.

“Although our results contrast those of other observational studies and [randomised] trials, considering the size and design of ACTT-3, it is unlikely that subcutaneous interferon beta-1a shows efficacy in patients [hospitalised] with COVID-19,” the authors wrote.

Study details

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

Andre C Kalil, Aneesh K Mehta, Thomas F Patterson, Nathaniel Erdmann, Carlos A Gomez, Mamta K Jain, et al.

Published in The Lancet on 18 October 2021

Summary

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 placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.

Interpretation
Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.

 

The Lancet study – Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial (Open access)

 

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