Tocilizumab

Repeat doses of tocilizumab is recommended for critically ill COVIDâ€Â19 patients

IL6 blockade could curb the

associated with a lower risk of death or ICU

Tocilizumab treatment was associated with significantly fewer events (including primary outcome) when compared to the (matched) control. Sample size: 106 + 140 control (or a 84 + 84 matched control). Dosage: single 400 mg dose. Endpoint: The composite of mortality and ventilation at day 28 (primary).

tocilizumab was associated with lower mortality despite higher superinfection occurrence

associated with reduction of the risk of ICU admission and death

Reduced mortality rate at day 30 compared to an a priori estimate. The benefit might be limited to patients without the need for mechanical ventilation at the baseline. Sample size: 180 + 528 (validation cohort; some data missing). Dosage: 8 mg/kg (up to 800 mg) single dose; second dose after 12 hours if respiratory function had not recovered.

Early adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in patients with COVID-19 pneumonia

not associated with reduced 30-day all-cause mortality, but shorter duration on ventilatory support as well as shorter overall length of stay in hospital and in ICU

Treatment with Tocilizumab can improve clinical symptoms and alleviate inflamation in critically ill patients. Dosage: 320 mg first dose (4-8 mg/kg); 240 mg second dose one patient and 640 mg another one. Sample size: 6.

Reduces 30-day unadjusted mortality rate (46% vs. 56% control). Sample size: 134 + 413 control. Dosage: A single dose in 78%, who received 400 mg (96%), 800 mg (1%), 8 mg/kg (1%), 4 mg/kg (1%), and missing dosing for 1%. Endpoint: 30-day mortality.

Clinical improvement and cytokine release syndrome amelioration in a case report of a critical patient. Dosage: Two doses of 8 mg/kg (450 mg) 12 hours apart.

Early administration of the drug lead to decrease in C reactive protein levels and increase in P/F ratio (partial pressure of oxygen to fraction of inspired oxygen) and prevented disease progression in moderately ill patients. Sample size: 10 + 10 control. Dosage: 324 mg.

Tocilizumab treatment (concomitant with antibiotics (azithromycin 500 mg/day), antivirals (lopinavir/ritonavir, eight patients; darunavir/cobicistat, four patients), and hydroxychloroquine (400 mg at suspicion/diagnosis followed by 400 mg after 12 h and 200 mg twice daily thereafter until day 5)) resulted after at most 10 days in supression of grade 4 cytokine release syndrome, increased oxygenation and lung radiographic improvement. Sample size: 12. Dosage: 324 mg; additional 324 mg 1-3 days later in 10 of the 12 patients. Endpoint: Incidence of grade 4 cytokine release syndrome.

Significantly shorter duration of vasopressor support and insignificant shortening of median time to clinical improvement and duration of invasive ventilation. Sample size: 28 + 23 control. Dosage: 400 mg single dose (concomitant systemic steroid, hydroxychloroquine, and azithromycin use).

Lowered mortality and/or requirement of invasive mechanical ventilation. Sample size: 30 + 176 control. Dosage: 8 mg/kg per dose, 1 or 2 doses.

Tocilizumab reduces inflammatory response to SARS-CoV-2 infection but does not impede humoral and cellular antiviral immune response mediated by plasma B cells and CD8+ T cells. Sample size: 2.

short-term survival benefit in patients with severe COVID-19 illness

Early tocilizumab treatment (optionally in combination with methylprednisolone) may improve clinical outcomes in non-intubated COVID-19 patients. Sample size: 29 + 56 with methylprednisolone + 66 control. Dosage: 8mg/kg intravenously or 162mg subcutaneously (+ optionally methylprednisolone 1 mg/kg for 5 days). Endpoint: Intubation/death-free survival.

Early administration in patients with worsening symptoms might provide laboratory and clinical improvement. Sample size: 3. Dosage: 400 mg.

effective when administrated before the need of high oxygen support

Rapid improvement in clinical parameters after Tocilizumab administration. Sample size: 1. Dosage: 664 mg (8 mg/kg).

Rapid improvement in clinical parameters after Tocilizumab administration in a boy aged 20 months with B-cell acute lymphoblastic leukaemia.

Patients in ICU treated with tocilizumab had reduced mortality. Sample size: 210 + 420 control. Dosage: 98% received 400 mg flat dosing, 1% received 8 mg/kg, and 1% received other doses; 88% received one infusion and 12% received a second infusion. Endpoint: Hospital-related mortality.

Patients with severe COVID-19 pnaeumonia treated with tocilizumab (either intravenously or subcutaneously) had a reduced risk of invasive mechanical ventilation or death. Sample size: 179 + 365 control. Dosage: 8 mg/kg (up to 800 mg) twice, 12 hours apart. Endpoint: A composite of death or invasive mechanical ventilation.

Early administration of tocilizumab (not depending on the route of administration) significantly improved survival and prevented hyper-inflammation. Sample size: 90 + 68 control. Dosage: 400 mg intravenous or 324 mg subcutaneous.

Significant decrease in the primary endpoint occurrence implies potential benefit for patients in a hyperinflammatory state. Sample size: 88 + 344 control. Dosage: See Table S2. Endpoint: Intubation or death rate at day 21.

Significant improvement in oxygen status, which did not result in improved survival, however. Sample size: 20 + 40 matched control. Dosage: 8 mg/kg IV single dose with an optional second one after at least 12 hours. Endpoints: De-escalation of oxygen therapy (primary); inâ€Âhospital death, septic shock, and acute kidney injury (AKI) requiring hemodialysis (secondary).

Favorable clinical outcome within a series of cases with severe COVID-19 pnaeumonia. Sample size: 5. Dosage: 400 or 800 mg single dose or two 400 or 600 mg doses.

Early administration of tocilizumab for severe COVID-19 patients may be beneficial. 83.33% of the treated severe to critical patients showed clinical improvement. Sample size: 42. Dosage: 400 mg single infusion. Endpoints: Changes in oxygenation support, need for invasive mechanical ventilation, and death (primary). Radiological changes in the lungs, IL-6 plasma levels, C-reactive protein levels, and adverse drug reactions (secondary).

In the majority of critically ill patients tocilizumab repressed clinical deterioration and led to clinical improvement. Some serious adverse treatment effects (e. g. candidemia) were observed, however. Sample size: 40. Dosage: 320-680 mg. Endpoints: Min. 50% decrease in FiO2; decrease in inflammatory markers; neutrophil to lymphocyte ratio; chest x-ray improvement.

Decrease of inflammation and good survival. Tocilizumab suggested for managing early cytokine release syndrome. Sample size: 30. Dosage: 4 mg/kg or 400 mg (optional second dose after 12+ hrs).

Decrease in respiratory rate, lower mechanical ventilation need incidence and signs of inflammation alleviation. Sample size: 22+ 22 control. Dosage: 600 mg for patients <100 kg and 800 mg for those >100 kg. Optional second dose after 48 hours. Endpoint: Respiratory clinical outcome (primary).

Increased survival in critical COVID-19 patients in the case of early tocilizumab administration (prior to or not later than one day after intubation). Sample size: 145. Dosage: Single dose (84.8%) or two doses (15.2%) of 4 mg/kg up to 400 mg (93.1%) or 600 mg (3.4%) or 800 mg (2.8%).

tocilizumab has beneficial effects in severe-to-critically ill patients with COVID-19; however, in some cases, addition of methylprednisolone is required for disease rescue

Clinical improvement in an eldelrly patient after the second dose of tocilizumab. Dosage: Two 8 mg/kg doses 12 hours apart.

Treatment resulted in a clinical improvement in a stage IV lung adenocarcinoma patient on chemoimmunotherapy. Some non-acute side effects occurred, though.

Tocilizumab treatment may be beneficial (clinical improvement) for some (but not all) severe to critical COVID-19 patients. Sample size: 19. Dosage: 8 mg/kg IV.

Improvement of clinical status (e.g. fever, cough, diarrhoea) together with inflammatory markers in a kidney transplant patient. Dosage: 400 mg IV.

Significantly decreased occurrence of both primary and secondary outcomes in patients with CRP >150 mg/L but not in those with  CRP ≤150 mg/L. Sample size: 261 + 969 control. Dosage: 600 mg (median). Endpoints: Time to death (primary); time to ICU admission or death (secondary).

Significantly lower rate of intubation or death in the treatment group. Sample size: 87 + 1138 control. Dosage: Single dose of 4â€Â8 mg/kg (second dose upon insufficient clinical response).

Clinical improvement (based on NEWS2 scoring, CRP levels and lymphocyte counts) in the patients not requiring mechanical ventilation. In mechanically ventilated patients, however, the numerical improvement in the CRP levels and NEWS2 scores did not translate into good survival outcome. Sample size: 89. Dosage: 400 mg IV.

Tocilizumab administration resolved acute biventricular heart failure associated with COVID-19-induced cytokine storm mimicking reverse Takotsubo syndrome in a patient. Dosage: 400 mg.

Good prognosis for severe but not critical patients (low probability of disease progression). In patients with high baseline oxygen requirements the treatment resulted in significantly worse outcome rate (intubation or death), however. Sample size: 186. Dosage: One (majority) or more doses of 400 mg (600 mg if body weight >75 kg).

Timely administration of tocilizumab significantly reduced the need for invasive mechanical ventilation and mortality in severe to critical COVID-19 patients. It also significantly reduced CRP levels in these patients. Sample size: 22 + 63 control. Dosage: 8 mg/kg (up to 800 mg total) divided in two doses 12 hours apart.

Lower mortality was observed at the follow-up (median day 27) in critically ill COVID-19 patients who received toculizumab within 2 days of ICU admission. Sample size: 433 (tocilizumab within 2 days of ICU admission) + 3491 control (no tocilizumab or administration later than 2 days after ICU admission).

The treatment might have reduced the rate of non-invasive ventilation, mechanical ventilation, or death by day 14. It did not significantly lower the proportion of patients who died by day 28 or reached WHO-CPS score higher than 5 at day 4, however. Sample size: 60 + 67 control. Dosage: 8 mg/kg single IV dose; 400 mg dose in some patients on day 3. Endpoints: Death or need for mechanical ventilation on day 4; survival without need for mechanical ventilation at day 14 (primary outcomes).

Improvement in pulmonary functions and vascular status and reduction of inflammatory markers in critical COVID-19 patients treated with tocilizumab. Sample size: 20 + 13 control. Dosage: Two IV doses of 8 mg/kg (up to 800 mg) 12-24 hours apart.

Improvement in some clinical parameters (fever, swelling, or mechanical ventilation need). No decrease in 30-day mortality was observed, however. Sample size: 75 (not all analyses). Dosage: IV 600 mg (body weight ≥ 75 kg) or 400 mg (patients < 75 kg); optional second and/or third dose in 12-hour interval.

Rapid improvement in coagulation and lowered inflammation markers in treated COVID-19 patients concomitant with improvement in respiratory function. Sample size: 70. Dosage: A single 324 mg subcutaneous dose.

Rapid clinical improvement after tocilizumab administration in a 44-year-old female without comorbities, who required mechanical velntilation due to COVID-19. Dosage: 400 mg IV.

Tocilizumab potentially alleviates cytokine release syndrome symptoms in COVID-19 patients. Some serious adverse effects (e.g. multidrug-resistant infections) were observed in the studied cohort, however. Sample size: 38. Dosage: 519 mg (average total).

In COVID-19 severe pneumonia patients tocilizumab administration was associated with significantly lower need of mechanical ventilation, higher rate of oxygen withdrawal and higher proportion of patients discharged from hospital by day 28. It was also associated with lowered CRP and fibrinogen levels post therapy. Despite higher neutropenia prevalence in treated patients, rates of infections were lower compared to the control group. Tocilizumab treatment did not significantly improve overall survival, but this could be due to study design/cohort structure. Sample size: 49 + 47 control. Dosage: Single 8 mg/kg IV dose; second dose 24-72 hours later if required.

Clinical improvement (oxygenation, CRP) 48 hours after tocilizumab administration in two thirds of the critical COVID-19 cases. 10 of the 12 patients could be later dischared, 2 patients died. Sample size: 12. Dosage: 8 mg/kg (majority); single dose (majority).

Decreased mortality, ICU admission and intubation rates, and CRP levels in the treated cohort. Sample size: 104. Dosage: Single dose of 600 mg (body weight ≥75 kg) or 400 mg (body weight <75 kg).

Low-dose tocilizumab treatment (40-200 mg, irrespective of the dose within the range) led to fever resolution and CRP decrease concomitant with IL-6 pathway mitigation in non-critical patients with COVID-19 pneumonia. Sample size: 32. Dosage: 40 to 200 mg single dose with optional second dose after 24 to 48 hours. Endpoints: Fever resolution and CRP decrease.

Despite significantly increased length of ICU stay and infection rate, tocilizumab-treated patients had significantly higher odds of survival compared to a matched control cohort. Sample size: 497 + 497 matched control. Dosage: Single 400 mg IV dose (optional second dose in few patients). Endpoint: Time to inpatient mortality (primary).
 

Administration of tocilizumab early after progression into severe status in patients not responding to antiviral therapy could improve the odds of survival. A patient who progressed into ARDS prior to tocilizumab administration (late diagnosis) died, however. Sample size: 3. Dosage: Two doses of 8 mg/kg 12 hours apart (a single dose in the patient who did not survive).

Significantly reduced mortality in tocilizumab-treated patients compared to control (both PS adjusted and unadjusted). The treatment appeared to provide the highest benefit to patients >65 years old with lymphocyte counts <1000 cells/μl, hypertension, and cardiovascular disease. Tocilizumab treatment combined with steroid administration reduced mortality significantly more than steroid treatment alone. Sample size: 268 + 238 control. Dosage: 600 mg median initial dose; 600 mg median cumulative dose (total 1 (57.4%) to 3 (8.2%) doses with median 1 day between 1st and 2nd and 2 days between 2nd and 3rd).

Tocilizumab administration in severe COVID-19 patients resulted in decrease in inflammation markers and was significantly associated with a lower risk of ARDS and lower in-hospital mortality. Sample size: 65 + 130 control. Dosage: 4-8 mg/kg single IV dose; optional second dose after 12 hours; optional third dose 24 hours after the second one. Endpoint: In-hospital death (primary outcome).

Considered by the authors to be among the most relevant drugs identified in a machine-learning algorithm-based screening of compounds which considers causal protein-protein interactions, known drug targets, and specific signalling circuits in

Significant reduction of primary outcome composite in the treated cohort compared to placebo. No treatment benefit with respect to death as the secondary outcome was detected, however. Sample size: 250 + 127 placebo (safety population). Dosage: 8 mg/kg single or two doses. Endpoint: Mechanical ventilation or death by day 28 (primary).

Improvement in certain clinical parametes was observed. Tocilizumab administration likely had positive impact on decreasing mortality in severe but not critical COVID-19 patients. Sample size: 86 severe + 40 critical. Dosage: Subcutaneously 324 mg (<100 kg bodyweight) or 486 mg (≥100 kg bodyweight).

Clinical improvement leading to hospital discharge was observed in a COVID-19 cytokine storm patient with aplastic anemia after Tocilizumab treatment. Dosage: 5 mg/kg.

Significantly increased primary outcome rate in combined therapy (with favipiravir) group, numerically increased rate in tocilizumab group compared to favipiravir group (potentially insignificant due to small sample size). Tocilizumab treatment (combinational) was effective in improvement of clinical symptoms, reduction of mortality and alleviation of inflammation. Sample size: 5 tocilizumab only + 14 combined with favipiravir + 7 favipiravir only. Dosage: A single infusion of 4−8 mg/kg (an optional second one when fever was not resolved within 24 hours). Endpoint: The cumulative lung lesion remission rate (primary).

Some clinical improvement was observed in the majority of patients after tocilizumab treatment; although, CRP rebound was observed, due to which administration of more doses was suggested. Sample size: 63. Dosage: A single dose of 4.75 mg/kg (average; 400 mg in majority). A second dose in 3 patients.

Peripheral blood mononuclear cells (PBMC) of kidney transplant patients were stimulated by CD3/CD28 to create an in vitro cytokine storm model. In patients who were undergoing tocilizumab treatment prior to PBMC donation, inflammatory pathways (overlapping with those observed in COVID-19-induced inflammation) were suppressed (as assayed by single-cell RNA sequencing).

In combination with methylprednisolone. The treatment was associated with a significant decrease in markers of inflammation and an increase in lymphocyte counts in critical COVID-19 patients. The observed ratio of severely or critically ill patients who were discharged from hospital (72%) and overall mortality (20%) were considered by the authors to be indicative of the treatment's efficacy.

Significant decrease of inflammatory markers (not D-dimer) was observed after tocilizumab administration. Improvement in respiratory parameters was observed, as well.  The number of patients on mechanical ventilation slightly decreased. 5 of the 25 patients in the study died. Sample size: 25. Dosage: Two IV doses of 400-800 mg 12-24 hours apart.

Treatment with tocilizumab in critically ill COVID-19 patients was associated with lower mortality compared to control. The difference in the rate of secondary infections between the groups was not statistically significant. Sample size: 55 + 41 control. Dosage: A single 400 mg IV dose. Primary outcome: Death rate.

Tocilizumab treatment was statistically associated with lower mortality (and numerical decrease in primary endpoint). Primary endpoind: Need for mechanical ventilation or death.

Combined with methylprednisolone. Reduced in-hospital mortality in severe COVID-19 pneumonia patients. Dosage: 400 mg (<75 kg body w.) or 600 mg (≥75 kg body w.) once or twice daily.

Significantly lower 14-day and 28- day mortality was observed among patients of ≥65 years of age with severe COVID-19 treated with corticosteroids combined with tocilizumab compared to those who were treated with corticosteroids only. Sample size: 80 tocilizumab and methylprednisolone + 181 methylprednisolone only. Dosage: One to three doses of 400–600 mg. Primary endpoint: All-cause mortality by day 14.

Although only numerical (statistically insignificant) improvement in the cure rate was observed, improvement in oxygenation and some other clinical parameters and reduction of disease worsening incidence was noted in the treated patients. The observed side effects were considered acceptable. Sample size: 34 + 31 control. Dosage: A single 400 mg IV dose; a second dose in 24 hours if still febrile. Primary outcome: The cure rate.

Administration of tocilizumab in severely to critically ill COVID-19 patients generally led to rapid improvement in fever and oxygenation. Temporal increase in IL-6 levels was observed, but the levels declined afterwards. Sample size: 30. Dosage: A single dose of 8 mg/kg or 400 mg.

A statistically significant improvement in mortality was observed in the group of critically ill COVID-19 patients after early tocilizumab treatment (within 1 day of intubation) compared to control. On the contrary, later administration of the drug resulted in a statistically significantly worse outcome compared to control. Sample size: 81 (of which 37 early and 44 late) + 37 control. Primary endpoint: Mortality.

Combined with umbilical cord-derived mesenchymal stem cells. The treatment was safe. Continual clinical improvement leading to recovery was observed. Sample size: 1. Dosage: 2 doses of 400 mg one day apart. 

The treatment appeared to alleviate inflammation, reduce oxygen and vasopressor support requirements, and reduce mortality. Some patients did not manifest rapid clinical improvement and had poorer outcomes, however. Sample size: 27. Dosage: A single 400 mg IV infusion. 

Reduced mortality without an increase in secondary infections was observed among the treated critically ill COVID-19 patients. Sample size: 55 + 41 control. Dosage: A single 400 mg IV infusion. Main outcome: Mortality.

The antibody reduced proinflammatory signalling factors’ expression in an in vitro model of inflammatory response. Severe (or critical) COVID-19 patients’ PAI-1 (a coagulation cascade activator) levels decreased upon tocilizumab treatment and an associated clinical improvement was observed. Sample size: 7. Dosage: A single dose of 400 mg. 

The previous baricitinib treatment did not improve patient’s clinical status. It was improved following tocilizumab administration. The improvement was only partial/temporal and further recovery was observed only after remdesivir administration. Sample size: 1. Dosage: 8 mg/kg. 

Although tocilizumab treatment in critically ill COVID-19 patients was associated with a decrease in CRP levels, the treatment did not result in clinical improvement. Sample size: 9 + 15 anakinra control. Dosage: 5 mg/kg twice a day. Main outcome: The clinical improvement at day 28 on an ordinal scale.

In the study cohort, the treatment was generally safe and led to improved survival. Sample size: 49 + 28 control. Dosage: 8 mg/kg (up to 800 mg) in two doses, 12 hours apart. 

Cytokine storm COVID-19 patients treated using corticosteroids (CS) together with tocilizumab showed lower mortality compared to those treated using CS alone or CS in combination with anakinra. Sample size: 1,383 CS only + 454 CS and tocilizumab + 733 CS and anakinra + 73 tocilizumab only + 57 anakinra only + 3,076 standard of care. Main outcome: Hospital mortality

The therapy increased survival in patients when initiated while PaO2/FiO2 ≥ 100 mmHg (but not if lower). Sample size: 30 + 103 matched control. Dosage: A single 400 mg IV dose; a second dose after 24 hours if the respiratory functions have worsened. 

Hospitalized kidney transplant patients who received anakinra or tocilizumab (AT) displayed better ordinal scale scores. Despite differences in rates of ICU admissions, secondary respiratory infections, or mortality were not significant compared to control, the authors suggest a possible benefit of AT therapy. Sample size: (14 + 4) pooled with anakinra + 15 control. Dosage: “...400 mg/24 h iv for patients with ≤75 kg and 600 mg/24 h intravenous (iv) for those with >75 kg, patients with no improvement could receive additional doses every 12 h up to a maximum of 3 doses.” 

A paediatric patient on ECMO was treated with remdesivir, methylprednisolone, IVIg, and anakinra. Sample size: 1. 

IL-blockers (pooled data for anakinra and tocilizumab) increased the odds of extubation. Sample size: 26 (+24 pooled with Anakinra) out of 382 (the whole assessed cohort). 

The treatment (data pooled for Tocilizumab and Sarilumab) did not significantly reduce mortality in the studied population. It was effective in the sub-cohorts of patients with either high levels of C-reactive protein or low levels of lactate dehydrogenase, however. Sample size: 29 (+ 26 pooled with Sarilumab) + 275 no IL-inhibitor. Dosage: A single IV dose of 400 mg (an optional second dose after 24 hours if respiratory functions had worsened). Main outcome: Survival.