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COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19.
medRxiv. 2020 Jul 26M

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.

Authors

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Pub Type(s)

Preprint

Language

eng

PubMed ID

32743594

Citation

Strohbehn, Garth W., et al. "COVIDOSE: Low-dose Tocilizumab in the Treatment of Covid-19." MedRxiv : the Preprint Server for Health Sciences, 2020.
Strohbehn GW, Heiss BL, Rouhani SJ, et al. COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19. medRxiv. 2020.
Strohbehn, G. W., Heiss, B. L., Rouhani, S. J., Trujillo, J. A., Yu, J., Kacew, A. J., Higgs, E. F., Bloodworth, J. C., Cabanov, A., Wright, R. C., Koziol, A., Weiss, A., Danahey, K., Karrison, T. G., Edens, C. C., Ventura, I. B., Pettit, N. N., Patel, B., Pisano, J., ... Reid, P. D. (2020). COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19. MedRxiv : the Preprint Server for Health Sciences. https://doi.org/10.1101/2020.07.20.20157503
Strohbehn GW, et al. COVIDOSE: Low-dose Tocilizumab in the Treatment of Covid-19. medRxiv. 2020 Jul 26; PubMed PMID: 32743594.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19. AU - Strohbehn,Garth W, AU - Heiss,Brian L, AU - Rouhani,Sherin J, AU - Trujillo,Jonathan A, AU - Yu,Jovian, AU - Kacew,Alec J, AU - Higgs,Emily F, AU - Bloodworth,Jeffrey C, AU - Cabanov,Alexandra, AU - Wright,Rachel C, AU - Koziol,Adriana, AU - Weiss,Alexandra, AU - Danahey,Keith, AU - Karrison,Theodore G, AU - Edens,Cuoghi C, AU - Ventura,Iazsmin Bauer, AU - Pettit,Natasha N, AU - Patel,Bhakti, AU - Pisano,Jennifer, AU - Strek,Mary E, AU - Gajewski,Thomas F, AU - Ratain,Mark J, AU - Reid,Pankti D, Y1 - 2020/07/26/ PY - 2020/8/4/entrez JF - medRxiv : the preprint server for health sciences JO - medRxiv N2 - 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. UR - https://www.unboundmedicine.com/medline/citation/32743594/COVIDOSE:_Low-dose_tocilizumab_in_the_treatment_of_Covid-19 DB - PRIME DP - Unbound Medicine ER -
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