{"doi":"10.1101/2020.07.20.20157503","title":"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 (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. Funding ClinicalTrials.gov number NCT04331795 . Study infrastructure was supported by NIH CTSA UL1 TR000430. Research in Context Evidence before this study Many 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 study This 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 evidence The 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.","journal":"medRxiv","year":2020,"id":119162,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9638,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":553604,"name":"Brian L. 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Koziol","orcid":null,"position":10,"is_corresponding":false},{"id":553609,"name":"Alexandra Weiss","orcid":"0000-0003-0169-6591","position":11,"is_corresponding":false},{"id":396011,"name":"Keith Danahey","orcid":"0000-0002-2418-855X","position":12,"is_corresponding":false},{"id":51395,"name":"Theodore Karrison","orcid":"0009-0009-8641-5111","position":13,"is_corresponding":false},{"id":296083,"name":"Cuoghi Edens","orcid":"0000-0002-2018-5044","position":14,"is_corresponding":false},{"id":553610,"name":"Iazsmin Bauer Ventura","orcid":"0000-0003-1306-4241","position":15,"is_corresponding":false},{"id":553611,"name":"Natasha N. Pettit","orcid":"0000-0002-8937-8039","position":16,"is_corresponding":false},{"id":74890,"name":"Bhakti K. Patel","orcid":"0000-0002-6517-2175","position":17,"is_corresponding":false},{"id":553612,"name":"Jennifer Pisano","orcid":"0000-0002-8156-3731","position":18,"is_corresponding":false},{"id":285957,"name":"Mary E. Strek","orcid":"0000-0002-7671-1023","position":19,"is_corresponding":false},{"id":92113,"name":"Thomas F. Gajewski","orcid":"0000-0001-5727-3972","position":20,"is_corresponding":false},{"id":356678,"name":"Mark J. Ratain","orcid":"0000-0002-0938-4392","position":21,"is_corresponding":false},{"id":553613,"name":"Pankti Reid","orcid":"0000-0002-7645-0919","position":22,"is_corresponding":false},{"id":535260,"name":"Garth W. 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