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

Autor: Cuoghi Edens, Pankti Reid, Rachel C Wright, Iazsmin Bauer Ventura, Jonathan A. Trujillo, Jennifer Pisano, Bhakti K. Patel, Mark J. Ratain, Keith Danahey, Mary E. Strek, Natasha N Pettit, Thomas F. Gajewski, Alexandra Cabanov, Sherin J. Rouhani, Garth W. Strohbehn, Jovian Yu, Brian L. Heiss, Theodore Karrison, Adriana Koziol, Emily F. Higgs, Alec Kacew, Jeffrey Bloodworth, Alexandra Weiss
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Clinical Pharmacology and Therapeutics
DOI: 10.1101/2020.07.20.20157503
Popis: BackgroundInterleukin-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.MethodsWe 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.FindingsA 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 (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.InterpretationLow-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.FundingClinicalTrials.gov number NCT04331795. Study infrastructure was supported by NIH CTSA UL1 TR000430.Research in ContextEvidence before this studyMany patients with novel coronavirus disease 2019 (Covid-19) develop acute lung injury and hypoxic respiratory failure possibly due to a hyperinflammatory state similar to the cytokine release syndrome that occurs as a complication of chimeric antigen receptor T-cell therapy. Interleukin-6 (IL-6) has been implicated in both processes, leading to the hypothesis that patients with Covid-19 may benefit from IL-6 axis-directed therapies such as the IL-6 receptor-blocking monoclonal antibody tocilizumab. No dose-finding studies have been performed for tocilizumab in the setting of Covid-19.Added value of this studyThis prospective phase 2 clinical trial is, to our knowledge, the first to evaluate low-dose tocilizumab in patients with Covid-19 and the first to evaluate the effect of tocilizumab on anti-SARS-CoV-2 antibody response.Implications of all the available evidenceThe COVIDOSE study, together with retrospective and real-world evidence studies demonstrating the efficacy of tocilizumab, suggests that low-dose tocilizumab is a potential treatment for hyperinflammation among patients with Covid-19 and merits randomized, controlled testing in this patient population.
Databáze: OpenAIRE
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