COVIDOSE: Low-dose tocilizumab in the treatment of COVID-19 pneumonitis

Background: Morbidity and mortality due to coronavirus disease 2019 (COVID-19) may in part be due tointerleukin-6 (IL-6)-mediated hyperinflammation The IL-6 receptor-targeted monoclonal antibody tocilizumab (TCZ)has been repurposed to treat COVID-19-related hyperinflammation, but prospective data are lacking Given TCZ'srisks of secondary infection and potential blunting of the adaptive immune response and its finite supply, study of theefficacy, safety, and dose response of TCZ for the treatment of COVID-19-related hyperinflammation is needed Methods: We conducted an adaptive phase 2 study of low-dose (LD) TCZ in hospitalized, non-mechanicallyventilated adult patients with COVID-19 pneumonitis and evidence of hyperinflammatory syndrome, with C-reactiveprotein (CRP) ≥ 40 micrograms per milliliter Dose cohorts were determined by a trial Operations Committee, withthe initial doses of 80 or 200 milligrams, depending on the magnitude of CRP elevation and epidemiologic riskfactors Doses were decreased to 40 mg and 120 mg after interim assessment The primary objective was to assessthe relationship of dose to clinical improvement in temperature and oxygen requirement and biochemical responseby CRP Results: 32 patients received LD TCZ 25 of 32 (78%) patients receiving LD TCZ at any dose achieved feverresolution In terms of dose-response, fever resolution in 24 hours was observed in 6 of 8 (75%) who received 200milligrams, 3 of 4 (75%) who received 120 milligrams, 11 of 15 (73%) who received 80 milligrams, and 5 of 5 (100%)who received 40 milligrams (p = 0 80 for response rate difference) Biochemical response consistent withinterleukin-6 pathway inhibition, corresponding to a ≥ 25% CRP decline, after a single dose of LD TCZ wasobserved in 5 of 8 (63%) who received 200 milligrams, 4 of 4 (100%) who received 120 milligrams, 10 of 15 (67%)who received 80 milligrams, and 5 of 5 (100%) who received 40 milligrams (p = 0 34 for response rate difference) 100% of patients achieved CRP response within two doses of LD TCZ Within the 28-day follow-up period, 5 (16%)patients died For patients who recovered, median time to clinical recovery was 4 days (interquartile range, 2-5) Clinically presumed and/or cultured bacterial superinfections were reported in 4 (12 5%) patients Correlativebiologic studies examining anti-SARS-CoV-2 antibody production across a range of TCZ doses are presentedseparately (abstract A-22514927) Conclusions: LD TCZ, in addition to standard of care, was associated with improvement of clinicalhyperinflammation parameters in hospitalized adult patients with COVID-19 pneumonitis No relationship betweenTCZ dose and clinical or biochemical response relationship was identified Results of the COVIDOSE trial provide arationale for a randomized, controlled trial of LD TCZ versus standard of care in those patients with COVID-19pneumonitis who have evidence of hyperinflammation (COVIDOSE, ClinicalTrials gov number, NCT04331795 )