tetano
Editor, Senior Moderator
Clin Microbiol Infect
. 2024 Jan 3:S1198-743X(24)00001-6.
doi: 10.1016/j.cmi.2023.12.028. Online ahead of print. Choosing immunomodulating therapies for the treatment of COVID-19: Recommendations based on placebo-controlled trial evidence
Daniel A Sweeney[SUP] 1 [/SUP], Suzana M Lobo[SUP] 2 [/SUP], Pedro Póvoa[SUP] 3 [/SUP], Andre C Kalil[SUP] 4 [/SUP]
Affiliations
Background: Immunomodulatory therapy has been extensively studied in randomized clinical trials for the treatment of patients hospitalized for COVID-19 with inconsistent findings. Guideline committees, reviewing the same clinical trial data, have generated different recommendations for immunomodulatory therapy.
Objectives: We hypothesize that trial design differences, specifically whether the study utilized an open-label or placebo-controlled design, accounted for the inconsistent mortality effects reported in clinical trials of immunomodulator therapies for COVID-19.
Sources: We reviewed COVID-19 treatment guidelines (WHO, IDSA and NIH) and identified the meta-analyses associated with glucocorticoids, IL-6 inhibitors, JAK kinase inhibitors, and complement C5a inhibitors that were available to the guideline authors at the time recommendations were either made or updated.
Content: We identified a meta-analysis for each of the immunomodulator classes that are included in current COVID-19 treatment guidelines: glucocorticoids (JAMA. 2021;326(6):499-518 cited 419), IL-6 antagonists (JAMA. 2021;326(6):499-518 cited 419), JAK inhibitors (Cochrane Database Syst Rev. 2022 Jun 13;6(6):CD015209 cited 34) and complement C5a inhibitors (Expert Review of Anti-infective Therapy, 21:1, 77-86 cited 1). Using the same RCTs, we evaluated the 4 meta-analyses accounting for trial design: placebo-controlled or open-label. Glucocorticoids (RR 0.91 [95% CI, 0.49-1.69]), IL-6 inhibitors sarilumab (RR 1.17 [95% CI, 0.96-01.43]) and tocilizumab (RR 0.95 [95% CI, 0.76-1.19]) did not reduce mortality in placebo-controlled trials, whereas baricitinib did confer a large survival benefit (RR 0.65, [95% CI 0.52-0.81]). The complement C5a inhibitor, vilobelimab, also reduced mortality in a single placebo-controlled trial (RR 0.76 [95% CI, 0.57-1.0]).
Implications: Placebo-controlled trial evidence indicates that baricitinib should be the first choice immunomodulator for patients hospitalized for COVID-19 who require any form of oxygen support-low or high-flow oxygen, non-invasive or invasive ventilation. Vilobelimab warrants study in a large placebo-controlled trial. Treatment guidelines for future pandemics should prioritize the results of placebo-controlled trials.
Keywords: Baricitinib; COVID-19; Coronavirus; IL-6 inhibitors; JAK inhibitors; SARS-CoV-2; Tocilizumab; complement inhibitors; glucocorticoids.
. 2024 Jan 3:S1198-743X(24)00001-6.
doi: 10.1016/j.cmi.2023.12.028. Online ahead of print. Choosing immunomodulating therapies for the treatment of COVID-19: Recommendations based on placebo-controlled trial evidence
Daniel A Sweeney[SUP] 1 [/SUP], Suzana M Lobo[SUP] 2 [/SUP], Pedro Póvoa[SUP] 3 [/SUP], Andre C Kalil[SUP] 4 [/SUP]
Affiliations
- PMID: 38182048
- DOI: 10.1016/j.cmi.2023.12.028
Background: Immunomodulatory therapy has been extensively studied in randomized clinical trials for the treatment of patients hospitalized for COVID-19 with inconsistent findings. Guideline committees, reviewing the same clinical trial data, have generated different recommendations for immunomodulatory therapy.
Objectives: We hypothesize that trial design differences, specifically whether the study utilized an open-label or placebo-controlled design, accounted for the inconsistent mortality effects reported in clinical trials of immunomodulator therapies for COVID-19.
Sources: We reviewed COVID-19 treatment guidelines (WHO, IDSA and NIH) and identified the meta-analyses associated with glucocorticoids, IL-6 inhibitors, JAK kinase inhibitors, and complement C5a inhibitors that were available to the guideline authors at the time recommendations were either made or updated.
Content: We identified a meta-analysis for each of the immunomodulator classes that are included in current COVID-19 treatment guidelines: glucocorticoids (JAMA. 2021;326(6):499-518 cited 419), IL-6 antagonists (JAMA. 2021;326(6):499-518 cited 419), JAK inhibitors (Cochrane Database Syst Rev. 2022 Jun 13;6(6):CD015209 cited 34) and complement C5a inhibitors (Expert Review of Anti-infective Therapy, 21:1, 77-86 cited 1). Using the same RCTs, we evaluated the 4 meta-analyses accounting for trial design: placebo-controlled or open-label. Glucocorticoids (RR 0.91 [95% CI, 0.49-1.69]), IL-6 inhibitors sarilumab (RR 1.17 [95% CI, 0.96-01.43]) and tocilizumab (RR 0.95 [95% CI, 0.76-1.19]) did not reduce mortality in placebo-controlled trials, whereas baricitinib did confer a large survival benefit (RR 0.65, [95% CI 0.52-0.81]). The complement C5a inhibitor, vilobelimab, also reduced mortality in a single placebo-controlled trial (RR 0.76 [95% CI, 0.57-1.0]).
Implications: Placebo-controlled trial evidence indicates that baricitinib should be the first choice immunomodulator for patients hospitalized for COVID-19 who require any form of oxygen support-low or high-flow oxygen, non-invasive or invasive ventilation. Vilobelimab warrants study in a large placebo-controlled trial. Treatment guidelines for future pandemics should prioritize the results of placebo-controlled trials.
Keywords: Baricitinib; COVID-19; Coronavirus; IL-6 inhibitors; JAK inhibitors; SARS-CoV-2; Tocilizumab; complement inhibitors; glucocorticoids.