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

Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with COVID-19, notably among those receiving high-flow oxygen or noninvasive ventilation, found the Adaptive Covid-19 Treatment Trial (ACTT-2), published in the New England Journal of Medicine. The combination was associated with fewer serious adverse events.

In a separate NEJM editorial, Dr Delia Goletti and Dr Fabrizio Cantini write: "By confirming the results of the previous open-label studies showing the beneficial effects of baricitinib for COVID-19 treatment, ACTT-2 provides the highest grade of evidence on the efficacy of the drug, which acts through the inhibition of JAK1 and JAK2 and consequently blocks the immune cascade and reduces viral replication.

"The reported highest efficacy of baricitinib in patients with ordinal scores of 5 and 6 allows expansion of the therapeutic armamentarium against COVID-19 pneumonia, mainly in patients receiving oxygen support without invasive mechanical ventilation Comparison between baricitinib and dexamethasone for the treatment of patients with Covid-19 pneumonia requiring supplemental oxygen would be an intriguing subject for future clinical research."

In May 2020, the first stage of the Adaptive Covid-19 Treatment Trial (ACTT-1), a randomised, double-blind, placebo-controlled trial, showed that remdesivir is an effective treatment for hospitalised adult patients with COVID-19)pneumonia. Despite the benefits of remdesivir, substantial morbidity and mortality due to COVID-19 remain.

Emerging data suggest that disease severity may be due in part to a dysregulated inflammatory response. It is postulated that mitigating the immune response and preventing a hyperinflammatory state may further improve clinical outcomes.

Baricitinib, an orally administered, selective inhibitor of Janus kinase (JAK) 1 and 2, was predicted with the use of artificial intelligence algorithms to be a potential therapeutic against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Baricitinib inhibits the intracellular signalling pathway of cytokines known to be elevated in severe COVID-19, including interleukin-2, interleukin-6, interleukin-10, interferon-γ, and granulocyte–macrophage colony-stimulating factor; acts against SARS-CoV-2 through the impairment of AP2-associated protein kinase 1 and the prevention of SARS-CoV-2 cellular entry and infectivity; and improves lymphocyte counts in patients with COVID-19.

In three case series of patients with COVID-19, baricitinib treatment was associated with both an improvement in oxygenation and a reduction in select inflammatory markers.

Randomised, controlled trials are needed to further understand the role of immunomodulation in patients with COVID-19.

After the successful completion of ACTT-1, we designed the next iteration of ACTT (ACTT-2) to evaluate whether the combination of baricitinib plus remdesivir was superior to remdesivir alone.


Study details
Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

Andre C Kalil, Thomas F Patterson, Aneesh K Mehta, Kay M Tomashek, Cameron R Wolfe, Varduhi Ghazaryan, Vincent C Marconi, Guillermo M Ruiz-Palacios, Lanny Hsieh, Susan Kline, Victor Tapson, Nicole M Iovine, Mamta K Jain, Daniel A Sweeney, Hana M El Sahly, Angela R Branche, Justino Regalado Pineda, David C Lye, Uriel Sandkovsky, Anne F Luetkemeyer, Stuart H Cohen, Robert W Finberg, Patrick EH Jackson, Babafemi Taiwo,
Catharine I Paules, Henry Arguinchona, Nathaniel Erdmann, Neera Ahuja, Maria Frank, Myoung-don Oh, Eu-Suk Kim, Seow Y Tan, Richard A Mularski, Henrik Nielsen, Philip O Ponce, Barbara S Taylor, LuAnn Larson, Nadine G Rouphael, Youssef Saklawi, Valeria D Cantos, Emily R Ko, John J. Engemann, Alpesh N Amin, Miki Watanabe, Joanne Billings, Marie-Carmelle Elie, Richard T Davey, Timothy H Burgess, Jennifer Ferreira, Michelle Green, Mat Makowski, Anabela Cardoso, Stephanie de Bono, Tyler Bonnett, Michael Proschan, Gregory A Deye, Walla Dempsey, P Seema U Nayak, Lori E Dodd, John H Beigel for the ACTT-2 Study Group Members*

Published in the NEJM on 4 March 2021

Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.
We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.
A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P=0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, −5.0 percentage points; 95% CI, −9.8 to −0.3; P=0.03), as were new infections (5.9% vs. 11.2%; difference, −5.3 percentage points; 95% CI, −8.7 to −1.9; P=0.003).
Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events.


[link url="https://www.nejm.org/doi/full/10.1056/NEJMoa2031994"]NEJM study (Open access)[/link]


[link url="https://www.nejm.org/doi/full/10.1056/NEJMe2034982?query=recirc_curatedRelated_article"]NEJM commentary (Open access)[/link]



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