COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19
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 <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</jats:ext-link> number <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04331795">NCT04331795</jats:ext-link>. 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..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 23. Apr. Zur Gesamtaufnahme - year:2024 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Strohbehn, Garth W. [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.1101/2020.07.20.20157503 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI018417787 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI018417787 | ||
| 003 | DE-627 | ||
| 005 | 20240424105126.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 200727s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2020.07.20.20157503 |2 doi | |
| 035 | |a (DE-627)XBI018417787 | ||
| 035 | |a (biorXiv)10.1101/2020.07.20.20157503 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Strohbehn, Garth W. |e verfasserin |0 (orcid)0000-0003-2973-3040 |4 aut | |
| 245 | 1 | 0 | |a COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19 |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a 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 <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</jats:ext-link> number <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT04331795">NCT04331795</jats:ext-link>. 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. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Heiss, Brian L. |e verfasserin |0 (orcid)0000-0002-7858-841X |4 aut | |
| 700 | 1 | |a Rouhani, Sherin J. |e verfasserin |0 (orcid)0000-0001-7248-847X |4 aut | |
| 700 | 1 | |a Trujillo, Jonathan A. |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jovian |e verfasserin |4 aut | |
| 700 | 1 | |a Kacew, Alec J. |e verfasserin |4 aut | |
| 700 | 1 | |a Higgs, Emily F. |e verfasserin |4 aut | |
| 700 | 1 | |a Bloodworth, Jeffrey C. |e verfasserin |4 aut | |
| 700 | 1 | |a Cabanov, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Wright, Rachel C. |e verfasserin |4 aut | |
| 700 | 1 | |a Koziol, Adriana K. |e verfasserin |4 aut | |
| 700 | 1 | |a Weiss, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Danahey, Keith |e verfasserin |4 aut | |
| 700 | 1 | |a Karrison, Theodore G. |e verfasserin |4 aut | |
| 700 | 1 | |a Edens, Cuoghi C. |e verfasserin |4 aut | |
| 700 | 1 | |a Ventura, Iazsmin Bauer |e verfasserin |4 aut | |
| 700 | 1 | |a Pettit, Natasha N. |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Bhakti K. |e verfasserin |4 aut | |
| 700 | 1 | |a Pisano, Jennifer |e verfasserin |0 (orcid)0000-0002-8156-3731 |4 aut | |
| 700 | 1 | |a Strek, Mary E. |e verfasserin |0 (orcid)0000-0002-7671-1023 |4 aut | |
| 700 | 1 | |a Gajewski, Thomas F. |e verfasserin |0 (orcid)0000-0001-5727-3972 |4 aut | |
| 700 | 1 | |a Ratain, Mark J. |e verfasserin |0 (orcid)0000-0002-0938-4392 |4 aut | |
| 700 | 1 | |a Reid, Pankti D. |e verfasserin |0 (orcid)0000-0002-7645-0919 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2024) vom: 23. Apr. |
| 773 | 1 | 8 | |g year:2024 |g day:23 |g month:04 |
| 856 | 4 | 0 | |u https://doi.org/10.1002/cpt.2117 |x 0 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2020.07.20.20157503 |x 0 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 23 |c 04 | ||