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11th March 2022
Giving baricitinib for 10 days to patients hospitalised with severe COVID-19 led to a 13% reduced risk of death compared with those in receipt of standard care. This was the main finding of the RECOVERY trial group at Oxford University, UK.
During the pandemic, several studies identified that a hyper-inflammatory response induced by the virus is a major cause of disease severity and death. Furthermore, data also indicates that glucocorticoids such as dexamethasone, can modulate this inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
Another factor which mediates inflammation in COVID-19 is interleukin-6, a cytokine produced by macrophages that induces a pro-inflammatory response and is often found to be elevated infected patients.
Baricitinib is a Janus Kinase (JAK) inhibitor and licensed for the treatment of both rheumatoid arthritis and atopic eczema. The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases.
Consequently, inhibition of this pathway with drugs such as baricitinib, represent a potentially useful therapeutic option for patients with COVID-19. In fact, there is already some evidence that while baricitinib does not reduce disease progression in COVID-19, it is associated with a mortality benefit.
For the current trial, which is available as a preprint, the RECOVERY team evaluated the effectiveness of baricitinib in a large number of patients, to further strengthen the evidence base for the drug. Patients were eligible for inclusion to the study if they had either confirmed or suspected COVID-19 and where their attending physician believed that inclusion did not pose a risk to the patient, e.g., because of their medical history.
Eligible patients were randomised 1:1 to either usual care plus baricitinib (10 mg daily for 10 days or until discharged if this was sooner) or usual care only. The primary outcome was 28-day all-cause mortality and secondary outcomes included time to discharge from hospital and a composite outcome of invasive mechanical ventilation or death among those not mechanically ventilated at the point of randomisation.
Baricitinib and mortality
A total of 8156 patients were included with 4148 (mean age 58.5 years, 66% male) randomised to baricitinib. Upon entry to the study, 95% of participants were receiving corticosteroids and 23% tocilizumab.
Among those allocated to baricitinib, the primary outcome occurred in 12% compared to 14% in the usual care group (adjusted rate ratio, RR = 0.87, 95% CI 0.77 – 0.98, p = 0.026). This reduction was similar (although non-significant) when adjusted for those with a confirmed positive PCR test (RR = 0.90, 95% CI 0.79 – 1.02).
In the baricitinib group, there was a lower risk of progression to the composite secondary outcome (RR = 0.90, 95% CI 0.81 – 0.99).
The authors concluded that their large randomised trial provided further and more robust evidence for the beneficial effects of baricitinib and support the use of the drug for patients hospitalised with COVID-19.
RECOVERY Collaborative Group. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. MedRxiv 2022
30th November 2020
On 19 November, 2020, the FDA gave emergency use authorisation for the baricitinib combination therapy to be used in patients hospitalised with either confirmed or suspected COVID-19, from 2 years of age and who require mechanical ventilation, supplemental oxygen or extracorporeal membrane oxygenation.
The approval is based on preliminary results from the ACCT-2 trial, which compared the recovery time in patients receiving either remdesivir alone or in combination with the JAK STAT inhibitor, baricitinib at a dose of 4mg. Remdesivir is already approved by the FDA as an antiviral drug for hospitalised COVID-19 patients, aged 12 years and over. Baricitinib is currently only licensed for use in rheumatoid arthritis but since the drug blocks the JAK-STAT intracellular messaging system, which is an important inflammatory pathway, there was a potential benefit from combining the two drugs. ACCT-2 was a Phase III trial that enrolled 1033 participants, who were randomised to either intravenous remdesivir alone plus matching placebo (518) or oral baricitinib (515). Remdesivir was given as a loading dose of 200mg, followed by 100 mg daily while in hospital, for up to 10 days. Baricitinib was given at a dose of 4mg per day and limited to a maximum of 14 days. All patients were assessed daily and if discharged, they were followed-up at home on days 15, 22 and at the study endpoint, day 29. Recovery from COVID-19 was defined as either being discharged from hospital, no longer requiring supplemental oxygen or needing ongoing medical care.
Preliminary data published from the trial showed that the median time to recovery with remdesivir and baricitinib was one day shorter (7 vs 8 days) than using remdesivir alone and this difference was statistically significant. In addition, the odds of a clinical improvement at day 15 using the combined therapy was also found to be significantly lower. Under the emergency use authorisation, the manufacturer of baricitinib, Eli Lilly, is required to provide both health professionals and patients, fact sheets which include information on dosing, side-effects and drug interactions. The full results of the ACCT-2 trial will be published in due course.