COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19

Abstract

Background Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking. Methods We conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) >= 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel. Findings A total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75.0% vs. 34.2%, p = 0.001) and CRP decline (86.2% vs. 14.3%, p < 0.001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related in this small study (p=0.80 and p=0.10, respectively). Within the 28-day follow-up, 5 (15.6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15.6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls. Interpretation Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.

Elevated markers of thrombo-inflammatory activation predict outcome in patients with cardiovascular comorbidities and COVID-19 disease: insights from the LEOSS registry

“…Indeed, clinical trials assessing the benefits of inflammatory cytokine blockade targeting IL-6 and its upstream mediator IL-1ß are in progress [9]. Given the heterogeneous preliminary results so far in trials applying IL-6 blockade in more severe cases of COVID-19 [22,23], the results of the present study may suggest to elucidate the specific role of IL-6 blockade in uncomplicated COVID-19 patients with cardiovascular comorbidities. Likewise, in light of the observed enhanced intravascular coagulation even during the uncomplicated phase of COVID-19 in patients with cardiovascular comorbidities, more aggressive anticoagulation treatment strategies may be warranted in these patients, as suggested in a recent retrospective analysis [24].…”

The systemic inflammatory response and clinicopathological characteristics in patients admitted to hospital with COVID-19 infection: Comparison of 2 consecutive cohorts

“…Other measures of the systemic inflammatory response such as the neutrophil lymphocyte ratio (NLR) have also been shown to have prognostic value (7). Moreover, the systemic inflammatory response has been shown to be a useful therapeutic target in patients with COVID-19 (8)(9)(10). However, to date, as there have been variations in the assessment of the systemic inflammatory response, other important factors may remain to be identified.…”

A Missing Link: Engagements of Dendritic Cells in the Pathogenesis of SARS-CoV-2 Infections

“…In fact, tocilizumab administration has been successful at immediately ameliorating clinical outcomes in patients with severe and critical disease [73]. A phase two clinical trial reported similar results, even with low doses of tocilizumab [74].…”