Dataset Information

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

ABSTRACT:

Objective

To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).

Design

Randomised, open label trial.

Setting

Nine hospitals in Brazil, 8 May to 17 July 2020.

Participants

Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group.

Interventions

Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64).

Main outcome measure

The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met.

Results

A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab.

Conclusions

In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.

Trial registration

ClinicalTrials.gov NCT04403685.

SUBMITTER: Veiga VC

PROVIDER: S-EPMC7815251 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

Veiga Viviane C VC Prats João A G G JAGG Farias Danielle L C DLC Rosa Regis G RG Dourado Leticia K LK Zampieri Fernando G FG Machado Flávia R FR Lopes Renato D RD Berwanger Otavio O Azevedo Luciano C P LCP Avezum Álvaro Á Lisboa Thiago C TC Rojas Salomón S O SSO Coelho Juliana C JC Leite Rodrigo T RT Carvalho Júlio C JC Andrade Luis E C LEC Sandes Alex F AF Pintão Maria C T MCT Castro Claudio G CG Santos Sueli V SV de Almeida Thiago M L TML Costa André N AN Gebara Otávio C E OCE de Freitas Flávio G Rezende FGR Pacheco Eduardo S ES Machado David J B DJB Martin Josiane J Conceição Fábio G FG Siqueira Suellen R R SRR Damiani Lucas P LP Ishihara Luciana M LM Schneider Daniel D de Souza Denise D Cavalcanti Alexandre B AB Scheinberg Phillip P

BMJ (Clinical research ed.) 20210120

<h4>Objective</h4>To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).<h4>Design</h4>Randomised, open label trial.<h4>Setting</h4>Nine hospitals in Brazil, 8 May to 17 July 2020.<h4>Participants</h4>Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). ...[more]

PMID: 33472855

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Project description:The primary objective was to evaluate ICU mortality at 28 days in patients with severe hypoxemic respiratory failure due to coronavirus disease 2019 infection who received tocilizumab. The secondary objectives were to evaluate ICU-, hospital-, mechanical ventilation-, and vasopressor-free days at day 28 and development of secondary infections.DesignRetrospective, observational, multicenter, cohort study between March 15, 2020, and May 31, 2020. Using propensity score matching based on ICU admission source, C-reactive protein, Sequential Organ Failure Assessment score, vasopressor use, age, race, weight, and mechanical ventilation, patients who received tocilizumab were matched to patients who did not receive tocilizumab.SettingTen hospitals within the Cleveland Clinic Enterprise.PatientsAdult patients admitted to a medical, surgical, neurosciences, or mixed ICU with severe acute respiratory syndrome coronavirus 2 infection.InterventionsNone.Measurements and main resultsFour-hundred forty-four patients were included: 342 patients (77%) did not receive tocilizumab and 102 patients (23%) received tocilizumab. Of those, 82 patients in each arm were matched. Before matching, patients who received tocilizumab had higher Sequential Organ Failure Assessment scores (6.1 ± 3.4 vs 4.7 ± 3.6), higher C-reactive protein (21.0 ± 10.2 vs 13.7 ± 9.6 mg/dL), higher frequency of intubation, vasopressor requirement, and paralytics. After matching, characteristics were more balanced and over 85% of patients required mechanical ventilation. ICU mortality was lower in tocilizumab group (23.2% vs 37.8%; risk difference, -15%; 95% CI, -29% to -1%), with more ICU-, hospital-, and vasoactive-free days at day 28 compared with those who did not receive tocilizumab. There was no difference in mechanical ventilation-free days at day 28 or development of secondary infections.ConclusionsTocilizumab use was associated with a significant decrease in ICU mortality in critically ill coronavirus disease 2019 patients with severe hypoxemic respiratory failure. Future randomized controlled trials limited to tocilizumab administration in critically ill coronavirus disease 2019 patients, with severe hypoxemic respiratory failure, are needed to support these findings.

Project description:BACKGROUND:As the novel SARS-CoV-2 pandemic occurred, no specific treatment was yet available. Inflammatory response secondary to viral infection might be the driver of severe diseases. We report the safety and efficacy (in terms of overall survival and hospital discharge) of the anti-IL6 tocilizumab (TCZ) in subjects with COVID-19. METHODS:This retrospective, single-center analysis included all the patients consecutively admitted to our Hospital with severe or critical COVID-19 who started TCZ treatment from March 13th to April 03rd, 2020. A 1:2 matching to patients not treated with TCZ was performed according to age, sex, severity of disease, P/F, Charlson Comorbidity Index and length of time between symptoms onset and hospital admittance. Descriptive statistics and non-parametric tests to compare the groups were applied. Kaplan Meier probability curves and Cox regression models for survival, hospital discharge and orotracheal intubation were used. RESULTS:Seventy-four patients treated with TCZ were matched with 148 matched controls. They were mainly males (81.5%), Caucasian (82.0%) and with a median age of 59 years. The majority (69.8%) showed critical stage COVID-19 disease. TCZ use was associated with a better overall survival (HR 0.499 [95% CI 0.262-0.952], p?=?0.035) compared to controls but with a longer hospital stay (HR 1.658 [95% CI 1.088-2.524], p?=?0.019) mainly due to biochemical, respiratory and infectious adverse events. DISCUSSION:TCZ use resulted potentially effective on COVID-19 in terms of overall survival. Caution is warranted given the potential occurrence of adverse events. FINANCIAL SUPPORT:Some of the tocilizumab doses used in the subjects included in this analysis were provided by the "Multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia" (EudraCT Number: 2020-001110-38) supported by the Italian National Agency for Drugs (AIFA). No specific funding support was planned for study design, data collection and analysis and manuscript writing of this paper.

Project description:BackgroundTocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series.Research questionThe goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19.Study design and methodsThis observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity.ResultsAmong the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002).InterpretationA treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.

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Dataset Information

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

Objective

Design

Setting

Participants

Interventions

Main outcome measure

Results

Conclusions

Trial registration

Publications

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

Similar Datasets

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