1. Publication
- Title: Tocilizumab, sarilumab and anakinra in critically ill patients with COVID-19: a randomised, controlled, open-label, adaptive platform trial
- Acronym: REMAP-CAP Immune Modulation Therapy Domain
- Year & Journal: Thorax, published July 15, 2025 (2025;80(8):530-539)
- Citation: Derde L, Gordon AC, Mouncey PR, et al; REMAP-CAP Investigators. Thorax. 2025;80(8):530-539. doi:10.1136/thorax-2024-222488
2. Context & Rationale
Background: IL-6 receptor antagonist tocilizumab was already shown to improve outcomes in critically ill COVID-19, but whether sarilumab (another IL-6 antagonist) and anakinra (IL-1 antagonist) were similarly effective — and whether these agents could be considered interchangeable amid drug shortages — remained unclear.
Research Question/Hypothesis: In critically ill COVID-19 patients receiving organ support, are sarilumab and anakinra as effective as tocilizumab (and standard care) at reducing duration of organ support and death?
3. Design & Methods
- Study Type: International, adaptive platform, randomized, controlled, open-label trial (REMAP-CAP)
- Setting & Centers: 133 sites, 9 countries; enrolled March 25, 2020 – April 10, 2021
- Population: Critically ill adults with COVID-19 receiving respiratory/cardiovascular organ support
- Intervention: Tocilizumab (n=972), sarilumab (n=485), or anakinra (n=378)
- Comparator: Standard care/control (n=418) (control arm closed Nov 19, 2020 once superiority trigger for tocilizumab was met)
- Randomization: Bayesian adaptive platform with predefined statistical triggers for superiority/equivalence/futility
- Blinding: Open-label
- Statistical Power & Follow-Up: Primary outcome: ordinal scale combining in-hospital mortality (worst category) and organ-support-free days to day 21.
4. Key Results
2274 critically ill participants enrolled (972 tocilizumab, 485 sarilumab, 378 anakinra, 418 control).
Outcome | Tocilizumab | Sarilumab | Anakinra | Control | Notes |
Median organ support-free days (primary) | 7 (IQR −1,16) | 9 (IQR −1,17) | 0 (IQR −1,15) | 0 (IQR −1,15) | — |
Adjusted OR vs control | 1.46 (95% CrI 1.13–1.87) | 1.50 (95% CrI 1.13–2.00) | 0.99 (95% CrI 0.74–1.35) | Reference | — |
Posterior probability of superiority vs control | 99.8% | 99.8% | 46.6% | — | Tocilizumab and sarilumab both clearly superior; anakinra not effective |
Statistical triggers met | Equivalence (tocilizumab=sarilumab) | Same | Inferiority to other active agents | — | Formal Bayesian triggers achieved during the trial |
Safety | Appeared safe | Appeared safe | Appeared safe | — | All treatments safe |
5. Internal Validity Assessment
Rigorous Bayesian adaptive platform design with prespecified statistical triggers for superiority, equivalence, and futility — methodologically sophisticated and efficient. Overall: Strong — large (2274-patient), international trial with formally met statistical triggers for both the tocilizumab/sarilumab equivalence finding and anakinra's inferiority; open-label design is a limitation, though the primary outcome (organ support-free days/mortality) is largely objective.
6. External Validity Assessment
International (133 sites, 9 countries) critically ill COVID-19 population on organ support — among the most externally valid COVID-19 immunomodulator trials given its scale and geographic diversity.
7. Strengths & Limitations
Strengths: First international adaptive trial directly comparing tocilizumab, sarilumab, and anakinra vs standard care; large sample; formal statistical triggers reduce ambiguity in interpretation; pragmatic, broadly applicable design.
Limitations: Open-label; continuing randomization without a fixed control group after closure introduces complexity from temporal confounders (variants, vaccination); anakinra's null result could reflect dosing, disease severity, or lack of early patient selection rather than true lack of efficacy.
8. Interpretation & Practice Impact
Confirms tocilizumab and sarilumab are equally effective and can be used interchangeably amid drug shortages — directly practice-relevant for supply-constrained health systems. Anakinra showed no benefit in this critically ill population, though this may reflect population/dosing/timing factors rather than a fundamental lack of IL-1-pathway relevance.
9. Controversies & Subsequent Evidence
The trial's own investigators note that continuing randomization without a control group (after closure) introduces potential bias from temporal changes (variants, vaccination) — an explicitly acknowledged methodological complexity of long-running adaptive platform trials. This is described as the first trial to provide direct head-to-head comparison between these specific immunomodulators.
10. Summary & Executive Takeaway
Summary: This REMAP-CAP domain trial randomized 2274 critically ill COVID-19 patients across 133 international sites to tocilizumab, sarilumab, anakinra, or control. Tocilizumab and sarilumab both significantly improved organ support-free days (adjusted OR 1.46 and 1.50, both >99.8% posterior probability of superiority), while anakinra showed no benefit (OR 0.99, 46.6% probability).
Overall Takeaway: Tocilizumab and sarilumab are equally effective immunomodulators for critically ill COVID-19 and can be used interchangeably during supply shortages, while anakinra shows no benefit in this population — the first direct, definitive head-to-head comparison of these three widely-used immunomodulatory agents.
11. Bibliography
- REMAP-CAP Investigators. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021;384:1491-1502.
- RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19. Lancet. 2021;397(10285):1637-1645.