Testing the efficacy of tocilizumab in patients with COVID-19 pneumonia

Abstract

Coronavirus infection (COVID-19) is affecting societies and economies globally. Developing therapies for hospitalized patients is therefore a matter of global urgency, in order to optimize care and outcomes. Investigators are working to identify molecular targets with a potential role in the development and outcome of adult respiratory distress syndrome in COVID-19, seeking pragmatic, novel and rational targets. This is being followed by rapidly designed randomized controlled trials (RCTs), with the subsequent aim of developing population-based recomendations. The common end points for this research include preventing intubation or death in hospitalized patients with COVID-19. In this context, the efficacy of tocilizumab in patients with COVID-19 has been examined in several randomized trials [1–6]. The trials differ significantly in their inclusion and exclusion criteria, enrolling patients with different disease severity at baseline. Commonly, researchers have reported that the confidence interval (CI) for efficacy comparisons are wide, so benefit or harm of treatment is uncertain. The trials did not show a difference in mortality between the tocilizumab and control groups. The efficacy end point of survival without invasive or noninvasive mechanical ventilation by day 14 was achieved in the CORIMUNO-TOCI-1 trial [4]; however, without a mortality benefit at day 28. The results of the trials suggest that patient enrollment criteria determine the benefit experienced with tocilizumab. Due to wide CIs, the conclusion is made in these trials that tocilizumab does not show efficacy. CIs are helpful in determining not only statistical significance but also the clinical relevance of findings. Hospitalized patients with COVID-19 display wide physiological and biological heterogeneity [7]. Wide CIs suggest how large the effect of a treatment could plausibly be. Thus, we cannot rule out the possibility that tocilizimab would help in certain groups of patients. In fact, a systematic review and meta-analysis reports that addition of tocilizumab to standard of care reduces mortality in severe COVID-19 [8]. On the other hand, a recent trial was stopped early by the data monitoring committee because of an increased number of deaths at 15 days in the tocilizumab group. This trial enrolled 129 patients with severe or critical COVID19 [9]. The study population included adults with confirmed COVID-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (CRP, D dimer, LDH or ferritin). However, the results from the Randomized, Embedded, Multifactorial Adaptive Platform Trial for CommunityAcquired Pneumonia (REMAP-CAP) found that in critically ill patients with COVID-19 requiring support in the ICU, treatment with the tocilizumab improved survival [10]. On 3 February 2021, the COVID-19 Treatment Guidelines Panel (the Panel) of NIH issued a statement on the use of tocilizumab in certain group of patients with COVID-19 based on the collective evidence from the REMAP-