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WHO 'strongly recommends' baricitinib for ventilated COVID patients

More critically ill COVID-19 patients on a mechanical ventilator or extracorporeal membrane oxygenation (ECMO) survived when randomised to receive baricitinib, compared with those on placebo, shows recent research.

Receiving the pill just once a day for up to 14 days yielded one of the largest survival advantages seen yet in the COVID pandemic, according to the study published in The Lancet Respiratory Medicine.

It is the first randomised study of the drug in ventilated ICU patients, half of whom received the study drug while the other received placebo. It is also the very drug predicted most likely to benefit COVID-19 patients in a recent AI study to determine which drugs could be repurposed to treat COVID-19.

“This study found that among COVID patients who were already critically ill on a mechanical ventilator, adding baricitinib (‘bari’) to usual care (steroids) saved lives,” said first author Dr E. Wes Ely, professor of Medicine and Critical Care at Vanderbilt University Medical Center and associate director of ageing research at the Nashville VA GRECC.

“At 60 days, 62% of patients given placebo had died versus only 45% of those receiving bari. This means that for every six people treated with bari as opposed to the placebo, one additional life was saved,” he said.

Baricitinib is an oral, selective Janus kinase (JAK) 1,2 inhibitor used in the treatment of rheumatoid arthritis that has previously shown efficacy in studies of hospitalised adults with COVID-19, including the COV-BARRIER multinational trial, with study patients enrolled from 101 sites in 12 countries.

In designing this investigation, Ely partnered with Dr Vince Marconi, professor of Infectious Diseases at Emory University. Marconi and colleagues had been interested in using JAK inhibitors for more than a decade to suppress inflammation in HIV. When the computer determined baricitinib was the prime suspect to save lives in COVID-19, it set the physician-scientists in motion with other collaborators at Eli Lilly and around the world.

“These data offer us a new tool in our armamentarium to help people live even if they are sick enough to require a breathing machine,” Ely said.

The study took place from 23 December 2020 to 10 April 2021, enrolling 101 participants, with 51 receiving baricitinib plus standard of care, and 50 receiving placebo plus standard of care.

Treatment with baricitinib significantly reduced all-cause mortality when compared with placebo, as 29 of the 50 participants (58%) died in the placebo group versus 20 of the 51 participants (39%) in the baricitinib group.

“This was a fairly small study of 100 patients done alongside our large phase III study of 1,525 patients in which we found similar lifesaving benefit for less sick hospitalised patients,” Ely said.

“Next, we need more clinical trials designed explicitly to determine how to improve survival for this subset of the world’s sickest COVID patients.”

The World Health Organization (WHO) recently updated its guidelines to “strongly recommend” baricitinib in combination with steroids to treat severe or critical COVID-19 patients, according to a report in The BMJ.

The COV-Barrier study was funded by Eli Lilly and Co., under license from Incyte Corp. As a result of this study, baricitinib is being made available free to low-to-middle income countries globally to aid in pandemic relief and in an effort to achieve equity in delivery of this lifesaving therapy.

Study details
Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial

E Wesley Ely, Athimalaipet Ramanan, Cynthia Kartman, Stephanie de Bono, Ran Liao, Maria Lucia Piruzeli, Jason Goldman, José Francisco Kerr Saraiva, Sujatro Chakladar, Vincent Marconi, Jorge Alatorre-Alexander, Javier David Altclas, Marcelo Casas, Valeria CevoliRecio, Todd Ellerin, Kleber Giovanni Luz, Jason Goldman, Maria Patelli Juliani Souza Lima, Akram Khan, Priscila Paulin, Ana Carolina Procopio Carvalho, Gustavo Rojas Velasco, Jose Francisco Kerr Saraiva, Imad Shawa, Jesus Simon Campos, Brian Tiffany, Adilson Westheimer Cavalcante.

Published in The Lancet Respiratory Medicine on 3 February 2022

Summary
Background
The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in studies of hospitalised adults with COVID-19. COV-BARRIER (NCT04421027) was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in critically ill hospitalised adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation.

Methods
This exploratory trial followed the study design of COV-BARRIER in a critically ill cohort not included in the main phase 3 trial. The study was conducted across 18 hospitals in Argentina, Brazil, Mexico, and the USA. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection on baseline invasive mechanical ventilation or extracorporeal membrane oxygenation were randomly assigned (1:1) to baricitinib (4 mg) or placebo once daily for up to 14 days in combination with standard of care. Participants, study staff, and investigators were masked to study group assignment. Prespecified endpoints included all-cause mortality through days 28 and 60, number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. The efficacy analysis was done in the intention-to-treat population and the safety analysis was done in the safety population.

Findings
Between Dec 23, 2020, and April 10, 2021, 101 participants were enrolled into the exploratory trial and assigned to baricitinib (n=51) or placebo (n=50) plus standard of care. Standard of care included baseline systemic corticosteroid use in 87 (86%) participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared with placebo (20 [39%] of 51 participants died in the baricitinib group vs 29 [58%] of 50 in the placebo group; hazard ratio [HR] 0·54 [95% CI 0·31–0·96]; p=0·030; 46% relative reduction; absolute risk reduction 19%). A significant reduction in 60-day mortality was also observed in the baricitinib group compared with the placebo group (23 [45%] events vs 31 [62%]; HR 0·56 [95% CI 0·33–0·97]; p=0·027; 44% relative reduction; absolute risk reduction 17%). In every six baricitinib-treated participants, one additional death was prevented compared with placebo at days 28 and 60. The number of ventilator-free days did not differ significantly between treatment groups (mean 8·1 days [SD 10·2] in the baricitinib group vs 5·5 days [8·4] in the placebo group; p=0·21). The mean duration of hospitalisation in baricitinib-treated participants was not significantly shorter than in placebo-treated participants (23·7 days [SD 7·1] vs 26·1 days [3·9]; p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment groups.

Interpretation
In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings.

The MBJ article
Covid-19: WHO recommends baricitinib and sotrovimab to treat patients

The Janus kinase (JAK) inhibitor baricitinib, which is also used to treat rheumatoid arthritis, is strongly recommended for patients with severe or critical COVID-19 in combination with corticosteroids, an expert group from the World Health OrganiSation has written in The BMJ.

WHO’s Guideline Development Group found moderate certainty evidence that baricitinib improved survival and reduced the need for ventilation, with no observed increase in adverse effects. Baricitinib has similar effects to interleukin 6 inhibitors, which are also used to treat arthritis, so when both drugs are available the expert group suggests choosing one on the basis of cost, availability, and clinician experience. It does not recommend using both drugs at the same time.

The group also advises against using two other JAK inhibitors—ruxolitinib and tofacitinib—in patients with severe or critical COVID-19 because evidence from small trials failed to show benefit and suggested a possible increase in serious side effects with tofacitinib.

The WHO group has also made a conditional recommendation for the use of the monoclonal antibody sotrovimab in patients with non-severe COVID-19, but only in those at highest risk of hospital admission, reflecting fewer benefits in those at lower risk.
Last December the UK’s Medicines and Healthcare Products Regulatory Agency approved sotrovimab for people aged over 12 with mild to moderate COVID-19 who were at high risk of developing severe disease, after it was shown to reduce the risk of hospital admission and death by 79% in high risk adults with symptomatic COVID-19.

Living guideline
WHO has already approved the monoclonal antibody casirivimab-imdevimab and found insufficient data to recommend one monoclonal antibody treatment over another. It also acknowledged that the effectiveness of these drugs against new variants such as omicron was still uncertain but said that it would update the guidelines when data became available.

The latest recommendations are based on evidence from seven trials involving over 4000 patients with non-severe, severe, and critical COVID-19. They add to previous recommendations for the use of interleukin 6 receptor blockers and systemic corticosteroids in patients with severe or critical COVID-19; conditional recommendations for the use of casirivimab-imdevimab, another monoclonal antibody treatment, in selected patients; and recommendations against the use of convalescent plasma, ivermectin, and hydroxychloroquine in patients with COVID-19 regardless of disease severity. The recommendations are part of a living guideline developed by WHO with the methodological support of the MAGIC Evidence Ecosystem Foundation.

 

The Lancet article – Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial (Open access)

 

The BMJ article – Covid-19: WHO recommends baricitinib and sotrovimab to treat patients (Open access)

 

See more from MedicalBrief archives:

 

Baricitinib plus remdesivir in reducing recovery time in COVID-19 patients — ACTT-2 trial

 

At last, serious efforts to repurpose generic drugs to treat COVID-19

 

Coronavirus: 'Promising new treatments must be explored immediately'

 

Antibody helps rid patients’ systems of SARS-Cov-2 sooner — Eli Lilly placebo trial

 

 

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