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Study of Interferon + Antivirals in COVID-19 Is First Published Randomized Trial with Positive Results

The FLARE Four

  • This open-label, multicenter randomized trial involved 127 patients in Hong Kong, where all patients who test positive for SARS-CoV-2 are hospitalized
  • Early triple therapy with interferon beta-1b, lopinavir–ritonavir and ribavirin was superior to lopinavir–ritonavir alone in shortening the duration of viral shedding, length of hospital stay and duration of symptoms in patients with mild to moderate COVID-19
  • Generalizability is limited by a lack of critically ill patients and variation in the time of treatment initiation with respect to symptom onset
  • Because of the inconsistent administration of interferon in the treatment group, more research is needed to determine the relative importance of each drug tested

The combination of interferon beta-1b, lopinavir–ritonavir and ribavirin has become the first COVID-19 therapy to show promising results in a published randomized trial in The LancetTiara Calhoun, MD, Internal Medicine and Global Medicine resident at Massachusetts General Hospital, reports and critiques the study in a fast literature update posted on May 11, 2020.


The viral load of SARS-CoV-2 peaks around the time that symptoms begin. The researchers hypothesized that early triple therapy might block the development of severe disease, as well as decrease the risk of transmitting the virus to other people.

Lopinavir is a protease inhibitor whose half-life increases when it is combined with ritonavir. Ribavirin is a guanosine nucleoside analog that interferes with viral replication. Interferons are part of the innate immune response to viral infection.

Study Details

The trial involved 127 adults at six hospitals across Hong Kong, where all patients who test positive for SARS-CoV-2 are hospitalized. Patients had to have symptom duration of ≤14 days. Within 48 hours of admission, they were randomly assigned to 14 days of study treatment and otherwise received standard care.

The researchers report on a "control group" and "combination group," but there were effectively three groups:

  • Triple therapy (52 patients first treated <7 days from symptom onset) — lopinavir–ritonavir, ribavirin and one to three doses of interferon beta-1b, depending on the number of days from symptom onset
  • Double therapy (34 patients first treated on day 7–14 of symptoms) — lopinavir–ritonavir and ribavirin; interferon was omitted to avoid its proinflammatory effects
  • Control group (41 patients) — lopinavir–ritonavir

Baseline characteristics of the study groups were approximately equivalent. No patients were critically ill at the time of randomization and only one was intubated during the study, which limits its generalizability.

Overall Results

  • Primary endpoint — Compared with the control group, the combination group (double and triple therapy groups analyzed together) had a significantly shorter median time from start of treatment to negative PCR test for SARS-CoV-2 (12 days vs. 7 days)
  • Secondary endpoints — No deaths occurred in either group within 30 days. All other endpoints were significantly better in the combination group, including time from treatment initiation to resolution of symptoms, time to SOFA score of 0 and length of hospital stay. There was no difference between groups in adverse events.

Subgroup Analysis

In a post hoc analysis, the researchers compared two subgroups:

  • Early — 76 patients (52 combination therapy, 24 control) who started treatment within 7 days of symptom onset and thus received interferon
  • Late — 51 patients (34 treatment therapy, 17 control) who started treatment ≥7 days after symptom onset and thus did not receive interferon

In the early subgroup, the results were similar to the overall analysis, but in the late subgroup, no significant differences were found between control and combination therapy.

Those findings suggest some component of the triple therapy was responsible for the benefits in the combination treatment group. Given the complicated distribution of treatments in the combination group, it's impossible to identify the component definitively.

However, since both the combination and control groups received lopinavir–ritonavir, it's likely that interferon, ribavirin or a synergistic effect of the three-drug combination was responsible for the improved outcomes.

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Learn more about COVID-19 clinical trials at Mass General

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