Baricitinib Plus Remdesivir for Hospitalized Adults With COVID-19
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
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Additional Info
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Baricitinib Plus Remdesivir for Hospitalized Adults With Covid-19
N. Engl. J. Med 2020 Dec 11;[EPub Ahead of Print], AC Kalil, TF Patterson, AK Mehta, KM Tomashek, CR Wolfe, V Ghazaryan, VC Marconi, GM Ruiz-Palacios, L Hsieh, S Kline, V Tapson, NM Iovine, MK Jain, DA Sweeney, HM El Sahly, AR Branche, J Regalado Pineda, DC Lye, U Sandkovsky, AF Luetkemeyer, SH Cohen, RW Finberg, PEH Jackson, B Taiwo, CI Paules, H Arguinchona, P Goepfert, N Ahuja, M Frank, MD Oh, ES Kim, SY Tan, RA Mularski, H Nielsen, PO Ponce, BS Taylor, L Larson, NG Rouphael, Y Saklawi, VD Cantos, ER Ko, JJ Engemann, AN Amin, M Watanabe, J Billings, MC Elie, RT Davey, TH Burgess, J Ferreira, M Green, M Makowski, A Cardoso, S de Bono, T Bonnett, M Proschan, GA Deye, W Dempsey, SU Nayak, LE Dodd, JH BeigelFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Combining an antiviral and an anti-inflammatory agent for COVID-19
When looking at articles dealing with a therapeutic intervention, my eyes gravitate to the flowsheet for enrollment and randomization, Kaplan-Meier curves, and rate ratio plots. Accordingly, in a recent paper dealing with therapy for COVID-19 pneumonia combining remdesivir with baricitinib [1], I paid close attention to these results. Baricitinib is an anti-inflammatory agent, targeting Janus kinase (JAK) 1 and 2. Adding an anti-inflammatory agent to an antiviral makes good sense with COVID-19 pneumonia, as the disease may be exacerbated by inflammatory responses.
This study built off the first stage of the Adaptive Covid-19 Treatment Trial, in which remdesivir was shown to be effective. In this second stage, using a multi-center, double-blinded, randomized controlled trial design, 1,033 patients were randomized to either standard therapy with remdesivir plus placebo or to remdesivir plus baricitinib. The two groups were well-balanced and had a high percentage of Latinx patients. Of note was that 30% of enrollees required non-invasive ventilation, high-flow oxygen therapy, mechanical ventilation, or extracorporeal membrane oxygenation.
Overall, patients receiving the combination therapy did better, recovering in 7 days as compared to 8 days (rate ratio for recover = 1.16; 95% CI: 1.01—1.32). In addition, they had higher levels of improvement at 15 days (Odds ratio = 1.3; CI: 1.0—1.6). When looking at the Kaplan-Meier curves and the rate ratio plots, however, most of the benefit is achieved in those patients that initially required non-invasive ventilation or high-flow oxygen therapy. Finally, combination therapy was associated with lower rates of serious adverse events and new infections than with remdesivir alone.
All told, combining baricitinib with remdesivir appears to be a reasonable option for those COVID-19 patients with pneumonia, and especially those requiring high-flow oxygen therapy or non-invasive ventilation. Baricitinib is provided orally or via nasogastric tube at a dose of 4 mg daily (with dose reduction for glomerular filtration rates of < 60 ml/minute) for 14 days or until hospital discharge.
References