Both corticosteroids and interleukin-6 receptor antagonists (IL-6ra) - tocilizumab and sarilumab - improve survival and reduce organ support needs in hospitalised COVID-19 patients, but their comparative effectiveness is unclear. Alternative treatments may be needed due to drug access issues.
Interleukin-1 (IL-1), involved in acute inflammation, is another therapeutic target, with anakinra (an IL-1 receptor antagonist) showing promise in moderately ill COVID-19 patients identified by biomarkers. Additionally, interferon-β, which may help protect the lungs, is being investigated.
The REMAP-CAP trial tested these immune modulators—tocilizumab, sarilumab, anakinra, and interferon-β—in critically ill COVID-19 patients and now reports final conclusions.
In the ongoing adaptive platform trial across 133 sites in 9 countries, critically ill COVID-19 patients were randomly assigned to receive tocilizumab, sarilumab, anakinra, or no immune modulator. The primary outcome combined in-hospital mortality (scored as –1) and days free of organ support up to day 21 for survivors. A Bayesian statistical model guided the trial, with predefined criteria to determine whether treatments were superior, inferior, effective, equivalent, or futile.
Among 2,274 critically ill patients enrolled, 972 received tocilizumab, 485 sarilumab, 378 anakinra, and 418 were controls. Median organ support–free days were 7 for tocilizumab, 9 for sarilumab, and 0 for both anakinra and control groups. Adjusted odds ratios for improved outcomes compared to control were 1.46 for tocilizumab, 1.50 for sarilumab, and 0.99 for anakinra. Tocilizumab and sarilumab showed a high probability (>99%) of superiority over control, while anakinra did not. All treatments were considered safe.
REMAP-CAP is the first international adaptive trial to directly compare tocilizumab, sarilumab, and anakinra versus standard care in critically ill COVID-19 patients on organ support. It confirmed that tocilizumab and sarilumab are equally effective, supporting their interchangeable use amid drug shortages. Anakinra showed no benefit in this critically ill group, possibly due to dosing, disease severity, or lack of early patient selection. The trial did not assess baricitinib, which other studies have linked to reduced mortality when added to standard care.
REMAP-CAP’s pragmatic, international design makes its findings broadly applicable to critically ill COVID-19 patients. The adaptive design allowed ongoing comparison of tocilizumab and sarilumab after removing the less effective control group, maximising learning while improving care. However, continuing randomisation without a control group introduces complexities, such as potential bias from temporal changes like virus variants and vaccination. The analysis accounted for these with time-adjusted models, making results generally robust, though caution is advised when interpreting some unadjusted data. The trial was open-label, but this likely did not affect mortality outcomes. Interferon-β1a was underrepresented and showed no benefit. Future research should explore other immune modulators like baricitinib and clarify which patients might benefit from anakinra, given contrasting trial results.
In conclusion, for adults with COVID-19 on organ support in intensive care, tocilizumab and sarilumab are equally effective at improving survival and shortening organ support duration, while anakinra is ineffective in this group.
Source: Thorax
Image Credit: iStock
