Eight randomized clinical trials of tocilizumab for treating patients with COVID-19 have reported heterogeneous results.1-6 Although 4 of them achieved their primary end point, improved 28-day survival was demonstrated only in the 2 largest studies and those with the highest mortality, RECOVERY1 and REMAP-CAP.2 Moreover, only RECOVERY enrolled only patients with elevated C-reactive protein (CRP) levels. The RECOVERY and REMAP-CAP trials involved a high rate of patients using dexamethasone (>80% of the patients in both treatment arms). Differences in trial outcomes may be associated with differences in power, populations, design, management, or length of follow-up.
We previously published a trial of tocilizumab in hospitalized patients who were receiving oxygen (rate, ≥3 L/min) but did not require high-flow or mechanical ventilation.3 The study met its primary composite end point, which was the proportion of patients who required noninvasive ventilation or intubation or who died at day 14, but found no survival difference at day 28. In this follow-up article, we extended follow-up to 90 days and examined whether survival varied with baseline CRP levels.
The details of the trial have been previously reported (Supplement 1 and Supplement 2).3 Institutional review board approval was provided by Comités de Protection des Personnes Île-de-France VI, and written informed consent was gained. In this follow-up article, we compared survival at 3 months using random-effects Cox models that were adjusted for age at randomization and center. We performed a post-hoc analysis that was stratified by CRP. Statistical analyses were conducted using R, version 3.6.4 (R Foundation).
By day 90, death had occurred in 7 of 63 (11%) and 11 of 67 patients (18%) in the tocilizumab and usual care arms, respectively (adjusted hazard ratio [HR], 0.64; 95% CI, 0.25-1.65) (Figure). When outcomes were analyzed according to CRP levels, we found a statistical interaction between CRP levels and the primary composite end point at day 14 and survival at day 90, with a benefit of tocilizumab in patients if their CRP levels were greater than 15.0 mg/dL (to convert to mg/L, multiply by 10), but not if CRP levels were 15.0 mg/dL or less. In patients with CRP levels greater than 15.0 mg/dL, the chance of achieving the primary end point (the percentage of patients who received noninvasive or invasive ventilation or those who died) was 18% and 57% in the tocilizumab and usual care groups, respectively (HR, 0.18; 95% CI, 0.06-0.59) (Table). Likewise, day-90 mortality was 9% and 35% in the tocilizumab and usual care groups, respectively (HR, 0.18; 95% CI, 0.04-0.89) (Table). Usual care could differ among centers and over time, and few patients were taking steroids at randomization (16% and 18% in the tocilizumab and usual care arms, respectively). The sample size was small and credibility intervals were wide. Lastly, in this trial, we targeted a narrow segment of the COVID-19 patient population (patients with a World Health Organization Clinical Performance Scale score of 5 exactly and requiring at least 3 L/min of oxygen), and our results are not generalizable to other populations.
This follow-up analysis suggests that tocilizumab may be considered for treating patients with moderate-to-severe COVID-19–associated pneumonia and high CRP levels. Further studies will help determine which patients with COVID-19–associated pneumonia would benefit the most from a combination of tocilizumab and dexamethasone.
Accepted for Publication: March 31, 2021.
Published Online: May 24, 2021. doi:10.1001/jamainternmed.2021.2209
Corresponding Author: Xavier Mariette, MD, PhD, Department of Rheumatology, Hôpital Bicêtre, 78 Av du Général Leclerc, 94275, Le Kremlin Bicêtre, France (xavier.mariette@aphp.fr).
Correction: This article was corrected on June 28, 2021, to fix an incorrectly named scale in the Results.
Author Contributions: Drs Porcher and Resche-Rigon had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Mariette, Hermine, Tharaux, Resche-Rigon, Ravaud.
Acquisition, analysis, or interpretation of data: Mariette, Tharaux, Resche-Rigon, Steg, Porcher, Ravaud.
Drafting of the manuscript: Mariette, Hermine, Tharaux.
Critical revision of the manuscript for important intellectual content: Mariette, Resche-Rigon, Steg, Porcher, Ravaud.
Statistical analysis: Resche-Rigon, Porcher, Ravaud.
Obtained funding: Mariette, Hermine, Resche-Rigon.
Administrative, technical, or material support: Resche-Rigon, Steg.
Supervision: Mariette, Hermine, Tharaux, Ravaud.
Conflict of Interest Disclosures: Dr Steg reported personal fees from Amarin, Amgen, AstraZeneca, BMS, Idorsia, Novo Nordisk, Novartis, Pfizer, Sanofi, Servier, and Regeneron as well as grants from Bayer, Sanofi, Servier, and Amarin outside the submitted work. Dr Ravaud reported being a minority shareholder of INATO outside the submitted work. No other disclosures were reported.
Funding: This trial was publicly funded (Ministry of Health, Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0143, PHRC COVID-19-20-0029] and Foundation for Medical Research).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We acknowledge the members of the CORIMUNO-19 collaborative group.
Data Sharing Statement: See Supplement 3.
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