Low-dose Tocilizumab Research Articles

A comparison of the effectiveness of different doses of tocilizumab and sarilumab in the treatment of severe COVID-19: a natural experiment due to drug shortages

ObjectivesInterleukin (IL)-6 inhibitors are administered to treat patients hospitalized with COVID-19. In 2021, due to shortages, different dosing regimens of tocilizumab, and a switch to sarilumab, were consecutively implemented. Using real-world data, we compare the effectiveness of these IL-6 inhibitors. MethodsHospitalized patients with COVID-19, treated with IL-6 inhibitors, were included in this natural experiment study. Sixty-day survival, hospital- and intensive care unit (ICU) length of stay, and progression to ICU or death were compared between 8 mg/kg tocilizumab, fixed-dose tocilizumab, low-dose tocilizumab, and fixed-dose sarilumab treatment groups. ResultsA total of 5485 patients from 49 hospitals were included. After correction for confounding, increased hazard ratios (HRs) for 60-day mortality were observed for fixed-dose tocilizumab (HR 1.20, 95% confidence interval [CI] 1.04-1.39), low-dose tocilizumab (HR 1.12, 95% CI 0.97-1.31), and sarilumab (HR 1.24, 95% CI 1.08-1.42), all relative to 8 mg/kg. The 8 mg/kg dosing regimen had lower odds of progression to ICU or death. Both hospital- and ICU length of stay were shorter for low-dose tocilizumab than for the 8 mg/kg group. ConclusionWe found differences in the probability of 60-day survival and the incidence of the combined outcome of mortality or ICU admission, mostly favoring 8 mg/kg tocilizumab. Because of potential time-associated residual confounding, further clinical studies are warranted.

Low-dose tocilizumab is associated with improved outcome and a low risk of secondary infection in severe COVID-19 pneumonia.

BackgroundRespiratory failure and death are the leading causes of severe Coronavirus disease 2019 (COVID‐19). Hyper‐inflammation and cytokine storm cause lung damage. This study aimed to compare the low‐dose and high‐dose effects of tocilizumab, an IL‐6 receptor antagonist.MethodPatients with severe pneumonia and hyper‐inflammation signs because of COVID‐19 were included in this retrospective study. Patients receiving tocilizumab <200 mg intravenously were classified as the low‐dose group, and receiving ≥200 mg as the high‐dose group, and those not treated with tocilizumab as the control group. Demographic and clinical data of patients who died and survived in both low‐high dose and control patients were compared. According to symptom day and radiological infiltration, patients with tocilizumab were also evaluated in two groups as early and late periods at tocilizumab administration time.ResultsA total of 160 patients were included in the study; 70 were treated with a low dose and 50 with high‐dose tocilizumab. Forty patients were in the control group. Age, comorbidity and clinical features were similar in the control, low‐dose tocilizumab and high‐dose tocilizumab groups. The mortality rate (12.9%, 30.0%, 37.5, P = .008) was less in the low‐dose tocilizumab group. The secondary infection rate was higher in the high‐dose group than in the low‐dose tocilizumab and control groups (44.0%, 10.0%, 10.0%, P < .001). Distinguishing between those patients who died and survived, age (OR: 1.1589, P < .001), higher APACHE II scores (OR: 1.225, P = .001) and needs for non‐invasive mechanical ventilation (OR: 14.469, P < .001) were the most critical risk factors. Low‐dose tocilizumab was associated with a lower mortality rate (OR: 0.244, P = .012).ConclusionThe use of tocilizumab at a low dose is associated with lower secondary infections and mortality.

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk.

BackgroundSevere hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven.ObjectivesThe primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure.MethodsA multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit.ResultsThe steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection.Conclusion and RelevanceCombination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.

Abstract S05-02: COVIDOSE: Low-dose tocilizumab in the treatment of COVID-19 pneumonitis

Abstract Background: Morbidity and mortality due to coronavirus disease 2019 (COVID-19) may in part be due to interleukin-6 (IL-6)-mediated hyperinflammation. The IL-6 receptor-targeted monoclonal antibody tocilizumab (TCZ) has been repurposed to treat COVID-19-related hyperinflammation, but prospective data are lacking. Given TCZ’s risks of secondary infection and potential blunting of the adaptive immune response and its finite supply, study of the efficacy, safety, and dose response of TCZ for the treatment of COVID-19-related hyperinflammation is needed. Methods: We conducted an adaptive phase 2 study of low-dose (LD) TCZ in hospitalized, non-mechanically ventilated adult patients with COVID-19 pneumonitis and evidence of hyperinflammatory syndrome, with C-reactive protein (CRP) ≥ 40 micrograms per milliliter. Dose cohorts were determined by a trial Operations Committee, with the initial doses of 80 or 200 milligrams, depending on the magnitude of CRP elevation and epidemiologic risk factors. Doses were decreased to 40 mg and 120 mg after interim assessment. The primary objective was to assess the relationship of dose to clinical improvement in temperature and oxygen requirement and biochemical response by CRP. Results: 32 patients received LD TCZ. 25 of 32 (78%) patients receiving LD TCZ at any dose achieved fever resolution. In terms of dose-response, fever resolution in 24 hours was observed in 6 of 8 (75%) who received 200 milligrams, 3 of 4 (75%) who received 120 milligrams, 11 of 15 (73%) who received 80 milligrams, and 5 of 5 (100%) who received 40 milligrams (p = 0.80 for response rate difference). Biochemical response consistent with interleukin-6 pathway inhibition, corresponding to a ≥ 25% CRP decline, after a single dose of LD TCZ was observed in 5 of 8 (63%) who received 200 milligrams, 4 of 4 (100%) who received 120 milligrams, 10 of 15 (67%) who received 80 milligrams, and 5 of 5 (100%) who received 40 milligrams (p = 0.34 for response rate difference). 100% of patients achieved CRP response within two doses of LD TCZ. Within the 28-day follow-up period, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 4 days (interquartile range, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 4 (12.5%) patients. Correlative biologic studies examining anti-SARS-CoV-2 antibody production across a range of TCZ doses are presented separately (abstract A-22514927). Conclusions: LD TCZ, in addition to standard of care, was associated with improvement of clinical hyperinflammation parameters in hospitalized adult patients with COVID-19 pneumonitis. No relationship between TCZ dose and clinical or biochemical response relationship was identified. Results of the COVIDOSE trial provide a rationale for a randomized, controlled trial of LD TCZ versus standard of care in those patients with COVID-19 pneumonitis who have evidence of hyperinflammation. (COVIDOSE, ClinicalTrials.gov number, NCT04331795.) Citation Format: Garth W. Strohbehn, Brian L. Heiss, Sherin J. Rouhani, Jonathan A. Trujillo, Athalia R. Pyzer, Jovian Yu, Alec J. Kacew, Alexandra Weiss, Spring Maleckar, Rachel Wright, Adriana Koziol, Bethany Martell, Keith Danahey, Theodore G. Karrison, Cuoghi Edens, Iazsmin Bauer Ventura, Natasha Pettit, Bakhti Patel, Jennifer Pisano, Mary Strek, Thomas F. Gajewski, Mark J. Ratain, Pankti D. Reid. COVIDOSE: Low-dose tocilizumab in the treatment of COVID-19 pneumonitis [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S05-02.

Low-dose subcutaneous tocilizumab to prevent disease progression in patients with moderate COVID-19 pneumonia and hyperinflammation

AimThis study aimed to evaluate the safety and efficacy profile of low-dose tocilizumab (TCZ), to prevent disease progression, subcutaneously administered to patients with moderate COVID-19 pneumonia and hyperinflammation. MethodsClinical characteristics and outcomes were retrospectively analysed of patients – with laboratory-confirmed bilateral COVID-19 pneumonia, hyperinflammation (C-reactive protein (CRP) ≥20 mg/dL), no hypoxaemia (oxygen saturation >90%), and no contraindications to TCZ – who were treated with subcutaneous TCZ (324 mg) administered within 48 h from hospitalization on top of standard of care (SOC). They were compared with matched controls treated with SOC only before TCZ was available at the institution. Clinical data were available for all patients until death or until day 35 for those discharged from hospital. FindingsTen consecutive patients (six males, median age 55 years) treated with TCZ on top of SOC, and ten patients (six males, median age 56 years) treated with SOC only were included. TCZ was well-tolerated with no clinically relevant adverse events. TCZ was associated with a reduction in CRP at day 1 (–50%, IQR –28 to –80) and day 3 (–89%, IQR –79 to –96; p = 0.005 for within-group), whereas there was no significant change in CRP values in the SOC group (p < 0.001 for between-group comparisons at both time points). TCZ resulted in a parallel improvement in oxygenation, as assessed by the ratio of partial pressure of oxygen to fraction of inspired oxygen (P/F) ratio, which increased at day 1 (+11%, IQR +6 to +16; p = 0.005 for within-group and p = 0.006 for between-group comparisons), and day 3 (+23%, IQR +16 to +34; p = 0.005 for within-group and p = 0.003 for between-group comparisons). None of the TCZ-treated patients had disease progression, defined as requirement of oxygen therapy or mechanical ventilation, whereas progression occurred in five (50%) patients among the SOC group. ConclusionsLow-dose subcutaneous TCZ may be a safe and promising therapeutic option administered on top of SOC to prevent disease progression in hospitalised patients with moderate COVID-19 and hyperinflammation.

Prevention of ovarian hyperstimulation syndrome in a rat model: comparison of the efficacy of tocilizumab with that of ranibizumab, cabergoline, and a gonadotropin-releasing hormone antagonist

The aim of the study is to investigate the effects of the interleukin-6 (IL-6) blocker tocilizumab in a hyperstimulated rat model and compare it with ranibizumab, a gonadotropin-releasing hormone antagonist (GnRHA), and cabergoline. Forty-seven rats were randomly divided into the following seven groups: Group 1: OHS; Group 2: OHS+ GnRHA; Group 3: OHS + ranibizumab; Group 4: OHS + cabergoline; Group 5: OHS + low-dose tocilizumab (TL); Group 6: OHS + high-dose tocilizumab (TH); Group 7: sham. Ovarian weight was significantly lower only in the ranibizumab group than in the OHS group. Estrogen levels were significantly lower in the GnRHA group than in the OHS and the treatment groups. Progesterone levels were significantly lower in the ranibizumab, cabergoline, and TL groups than in the OHS group. Among the treatment groups, corpus luteum counts were lower than in the OHS group. Corpus luteum counts were lowest in the tocilizumab groups. IL-6 intensity was lower in all treatment groups than in the OHS group. In the ranibizumab group IL-6 intensity was the lowest. The TL group did not significantly differ from the GnRHA and cabergoline groups regarding IL-6 expression. Ovarian VEGF expression was significantly lower in all treatment groups. For the TL, ranibizumab, and cabergoline groups VEGF intensity was similar. Tocilizumab may be a new strategy for preventing ovarian hyperstimulation syndrome by inhibition of IL-6.