COVIDOSE: A Phase II Clinical Trial of Low‐Dose Tocilizumab in the Treatment of Noncritical COVID‐19 Pneumonia
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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.
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SciScore for 10.1101/2020.07.20.20157503: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The UCM institutional review board (IRB) approved the trial protocol.
Consent: Patients or their legally authorized representatives provided written or electronic informed consent.Randomization Our trial lacked a contemporaneous, randomized comparator arm, and the higher rate of epidemiologic risk factors in the retrospective control population may have contributed to its slow recovery in terms of both fever resolution and CRP decline. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources 27 Goat anti-human immunoglobulin (Ig)-Horseradish … SciScore for 10.1101/2020.07.20.20157503: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The UCM institutional review board (IRB) approved the trial protocol.
Consent: Patients or their legally authorized representatives provided written or electronic informed consent.Randomization Our trial lacked a contemporaneous, randomized comparator arm, and the higher rate of epidemiologic risk factors in the retrospective control population may have contributed to its slow recovery in terms of both fever resolution and CRP decline. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources 27 Goat anti-human immunoglobulin (Ig)-Horseradish peroxidase (HRP) reactive to heavy and light chains of human IgG, IgM, and IgA was used as the secondary antibody (SouthernBiotech; Birmingham, AL, USA). anti-human immunoglobulinsuggested: NoneAntibody titers were determined by measuring total immunoglobulin (IgG, IgM, IgA) reactive against the SARS-CoV-2 Spike glycoprotein and its receptor-binding domain (RBD). total immunoglobulin ( IgGsuggested: NoneIgM , IgAsuggested: NoneSARS-CoV-2 Spike glycoprotein and its receptor-binding domain ( RBD) .suggested: None27 Specifically, the RBD protein binds the angiotensin-converting enzyme 2 (ACE2) receptor on human cells, and likely serves as a target for neutralizing antibodies that facilitate virus clearance. ACE2suggested: NoneLog10 titers of anti-SARS-CoV-2 antibodies in the tocilizumab-treated and untreated populations were compared using Welch’s t-test in R (R Foundation for Statistical Computing; Vienna, Austria). anti-SARS-CoV-2suggested: NoneAfter 3 washes in 0·05% PBS-Tween 20, a goat anti-human immunoglobulin (Ig)-Horseradish peroxidase (HRP) conjugated secondary antibody (SouthernBiotech, Catalog #2010-05, Lot #C2117-T819E), reactive to heavy and light chains of human IgG, IgM, and IgA, was diluted in 1% milk in 0·1% PBS-Tween-20, and added at 1:8000 for 1 hour at room temperature. a goat anti-human immunoglobulinsuggested: NoneIgAsuggested: NoneExperimental Models: Cell Lines Sentences Resources 3 Recombinant proteins were produced using a Chinese hamster ovary (CHO) cell line expression system and purified using metal-chelate affinity chromatography. Chinese hamster ovary (CHO)suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04331795 Completed Tocilizumab to Prevent Clinical Decompensation in Hospitaliz… Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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