COVIDOSE: A Phase II Clinical Trial of Low-Dose Tocilizumab in the Treatment of Noncritical COVID-19 Pneumonia

Garth W Strohbehn, Brian L Heiss, Sherin J Rouhani, Jonathan A Trujillo, Jovian Yu, Alec J Kacew, Emily F Higgs, Jeffrey C Bloodworth, Alexandra Cabanov, Rachel C Wright, Adriana K Koziol, Alexandra Weiss, Keith Danahey, Theodore G Karrison, Cuoghi C Edens, Iazsmin Bauer Ventura, Natasha N Pettit, Bhakti K Patel, Jennifer Pisano, Mary E Strek, Thomas F Gajewski, Mark J Ratain, Pankti D Reid, Garth W Strohbehn, Brian L Heiss, Sherin J Rouhani, Jonathan A Trujillo, Jovian Yu, Alec J Kacew, Emily F Higgs, Jeffrey C Bloodworth, Alexandra Cabanov, Rachel C Wright, Adriana K Koziol, Alexandra Weiss, Keith Danahey, Theodore G Karrison, Cuoghi C Edens, Iazsmin Bauer Ventura, Natasha N Pettit, Bhakti K Patel, Jennifer Pisano, Mary E Strek, Thomas F Gajewski, Mark J Ratain, Pankti D Reid

Abstract

Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the mortality of coronavirus disease 2019 (COVID-19). The IL-6 receptor-blocking monoclonal antibody tocilizumab has been repurposed for COVID-19, but prospective trials and dose-finding studies in COVID-19 have not yet fully reported. We conducted a single-arm phase II trial of low-dose tocilizumab in nonintubated hospitalized adult patients with COVID-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) ≥ 40 mg/L. We hypothesized that doses significantly lower than the emerging standards of 400 mg or 8 mg/kg would resolve clinical and laboratory indicators of hyperinflammation. A dose range from 40 to 200 mg was evaluated, with allowance for one repeat dose at 24 to 48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Thirty-two patients received low-dose tocilizumab, with the majority experiencing fever resolution (75%) and CRP decline consistent with IL-6 pathway abrogation (86%) in the 24-48 hours following drug administration. There was no evidence of a relationship between dose and fever resolution or CRP decline over the dose range of 40-200 mg. Within the 28-day follow-up, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 3 days (interquartile range, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (16%) patients. 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 provide rationale for a randomized, controlled trial of low-dose tocilizumab in COVID-19.

Conflict of interest statement

G.W.S. is supported by the Richard and Debra Gonzalez Research Fellowship at the University of Chicago (established through philanthropy by Abbott Laboratories; Lake Bluff, Illinois, USA). B.L.H. is funded by the T32 GM007019 grant from the National Institute of General Medical Sciences. M.E.S. reports research grants from Boerhinger Ingelheim, Galapagos and Novartis and personal fees from Boerhinger Ingelheim and Genentech. M.J.R. reports other support including the following: personal fees from multiple generic companies, personal fees from Cyclacel, personal fees from Aptevo, personal fees from Shionogi, other from Dicerna, personal fees and other from Genentech, other from BeiGene, other from AbbVie, other from Corvus, other from Bristol‐Myers Squibb, other from Xencor, outside the submitted work. In addition, M.J.R. has a patent US6395481B1 with royalties paid to Mayo Medical, a patent EP1629111B1 with royalties paid to Mayo Medical, a patent US8877723B2 issued, a patent US9617583B2 issued, and a patent provisional patent pending and Director and Treasurer, Value in Cancer Care Consortium. G.W.S., B.L.H., P.D.R., and M.J.R. are coinventors of a filed provisional patent on the use of low‐dose tocilizumab in viral infections. All other authors declared no competing interests for this work.

© 2020 The Authors. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Flow of patients in the COVIDOSE trial. Thirty‐two eligible patients consented to participate in the COVIDOSE trial, of which 12 were assigned to Group A and 20 were assigned to Group B on the bases of magnitude of C‐reactive protein elevation and epidemiologic risk factors for COVID‐19 related mortality. Group A patients received either 200 or 120 mg of tocilizumab and were followed for 28 days following drug administration. Group B patients received either 80 or 40 mg of tocilizumab and were followed for 28 days following drug administration. All 32 patients were evaluable for the purposes of primary clinical outcome and 29 were evaluable for biochemical outcome. No patients were lost to follow‐up.
Figure 2
Figure 2
Temperature and CRP decrease rapidly following administration of low‐dose tocilizumab. (a) Temperature values for COVIDOSE patients following eligibility (mean ± standard error of mean). (b) Percentage of COVIDOSE (dark gray), COVIDOSE Group A (light gray), and COVIDOSE Group B (white) patients meeting the primary outcome of Tmax24 hours < 38.0°C. (c) Relationship between tocilizumab dose and probability of achieving fever resolution. Percentage of COVIDOSE patients at the noted tocilizumab dose levels achieving the outcome of Tmax24 hours < 38.0°C. Bars denote one‐sided Fisher exact test for difference in proportions. P values are as shown in the panel. (d) Representative CRP values for COVIDOSE patients following eligibility (mean ± standard error of mean). (e) Percentage of COVIDOSE (dark gray), COVIDOSE Group A (light gray), and COVIDOSE Group B (white) patients meeting the primary biochemical outcome of CRP decline of ≥ 25% at 24 hours. (f) Relationship between tocilizumab dose and probability of achieving CRP decline of ≥ 25%. Percentage of COVIDOSE patients at the noted tocilizumab dose levels achieving CRP decline of ≥ 25%. Bars denote one‐sided Fisher exact test for difference in proportions. P values are as shown in the panel figure. CRP, C‐reactive protein; Tmax24 hours, maximum temperature within 24 hours following drug administration.

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Source: PubMed

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