Abstract
This follow-up study of the CORIMUNO-TOCI-1 randomized clinical trial examines the association between survival and C-reactive protein levels in patients hospitalized with COVID-19 who were treated with tocilizumab.
Eight randomized clinical trials of tocilizumab for treating patients with COVID-19 have reported heterogeneous results.1,2,3,4,5,6 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.
Methods
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).
Results
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.
Figure. Overall Survival Up to Day 90 in the CORIMUNO-TOCI-1 Trial.
CRP indicates C-reactive protein.
Table. Outcomes According to Baseline CRP Level.
| Characteristic | No./total No. (%)a | Adjusted HR (95% CI) | |
|---|---|---|---|
| Tocilizumab (n = 63) | Usual care (n = 67) | ||
| Received noninvasive or invasive ventilation or death until day 14 | |||
| CRP, >15.0 mg/dL | 4/22 (18) | 13/23 (57) | 0.18 (0.06-0.59) |
| CRP, ≤15.0 mg/dL | 8/34 (24) | 9/40 (23) | 0.99 (0.38-2.56) |
| P value for interaction | NA | NA | .045 |
| Death until day 90 | |||
| CRP, >15.0 mg/dL | 2/22 (9) | 8/23 (35) | 0.18 (0.04-0.89) |
| CRP, ≤15.0 mg/dL | 3/34 (9) | 1/402 | NA |
| P value for interaction | NA | NA | .02 |
Abbreviations: CRP, C-reactive protein; HR, hazard ratio; NA, not applicable (too low No. of events).
SI conversion factor: To convert CRP to mg/L, multiply by 10.
Eleven participants had missing CRP data at baseline. Data presented are deaths/denominator and Kaplan-Meier event probability. The HR is adjusted for age and center.
Discussion
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.
Trial protocol
Statistical analysis plan
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
Statistical analysis plan
Data sharing statement
