Clinical Trial Has Found Interferon Does Not Help Adults Hospitalized With COVID-19

Colorized scanning electron micrograph of a human cell heavily infected with SARS-CoV-2 virus particles (red). Image captured at the NIAID Integrated Research Facility in Fort Detrick, Maryland. Credit: NIAID

A clinical trial showed that treatment with the immunomodulator interferon beta-1a plus the antiviral remdesivir was not superior to treatment with remdesivir alone in hospitalized adults with COVID-19 pneumonia. In addition, in a subset of patients requiring high-flow oxygen, the researchers found that interferon beta-1a was associated with more side effects and worse outcomes. These findings are published today (Oct. 18, 2021) in the journal The Lancet Respiratory Medicine.

The study, called the Adaptive COVID-19 Treatment Trial 3 (ACTT-3), took place from August 5, 2020 to December 21, 2020. It was sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Interferon beta-1a has the same amino acid sequence as a naturally occurring protein called interferon beta, which is part of a class of proteins called type 1 interferons. Infected cells normally produce type 1 interferons to help the immune system fight off pathogens, especially viruses. Interferon beta has both antiviral and anti-inflammatory properties.

Laboratory studies have shown that the normal type 1 interferon response is suppressed after infection with SARS-CoV-2, the virus that causes COVID-19. In addition, previous studies of hospitalized patients with COVID-19 showed decreased interferon production in response to SARS-CoV-2 infection in many patients, and this was associated with more severe disease. Other lab studies and clinical data supported the hypothesis that interferon beta-1a treatment could improve health outcomes in people with COVID-19.

Ultimately, however, the ACTT-3 researchers found that interferon beta-1a plus remdesivir was not associated with a clinical benefit compared to remdesivir alone in adults hospitalized with COVID-19. The primary outcome, time to recovery, was the same – a median of 5 days – for participants who received interferon beta-1a plus remdesivir as for those who received remdesivir alone. The likelihood of clinical improvement at day 15 was also similar for participants in the two treatment groups.

Remdesivir was used as an active control in this study because the first repeat of the ACTT studies showed that the antiviral drug was superior to placebo in reducing recovery time in adults hospitalized with COVID-19.

The ACTT-3 research team enrolled 969 adults at 63 locations in the United States, Japan, Mexico, Singapore and South Korea. Sixty percent of patients were Caucasian, 17% were Black, 9% were Asian, 1% were Native American or Alaskan Native, and 32% were Hispanic or Latino. Participants were randomly assigned in a 1-to-1 ratio to receive either interferon beta-1a plus remdesivir or placebo plus remdesivir. Neither the participants nor the research team knew who received which treatment regimen until the end of the trial.

On September 4, 2020, the study was amended to stop enrolling participants with severe COVID-19 who required high-flow oxygen and to exclude people who required non-invasive or invasive mechanical ventilation. These changes were made after the study’s Data and Safety Monitoring Board (DSMB) noted a higher number of serious adverse events, most notably worsening respiratory status, in participants requiring high-flow oxygen at enrollment and receiving interferon beta-1a. compared to those who did. not receive interferon beta-1a. The ACTT-3 researchers speculate that interferon may have increased the inflammatory response, leading to more severe respiratory disease in these participants. However, the researchers note that this worse outcome may have been influenced by baseline imbalances between the interferon and control groups.

Reference: “Efficacy of interferon beta-1a plus remdesivir compared to remdesivir alone in hospitalized adults with COVID-19: a phase 3 double-bind, randomized, placebo-controlled trial” Oct. 18, 2021, The Lancet Respiratory Medicine.
DOI: 10.116/S2213-2600(21)00412-4

Subcutaneous interferon beta-1a is a multiple sclerosis drug manufactured in the United States and marketed under the brand name Rebif by EMD Serono Inc., the biopharmaceutical company of Merck KGaA, Darmstadt, Germany. Remdesivir, also known as Veklury, is manufactured by Gilead Sciences, Inc. in Foster City, California.

Additional information on ACTT-3 is available on ClinicalTrials.gov under study identifier NCT04492475.