Tocilizumab

Tocilizumab is a monoclonal antibody that targets both soluble and membrane bound IL-6 receptors, preventing IL-6 binding and reducing IL-6 signaling. It is used in treatment of autoimmune diseases and hyper-inflammatory states, such as CAR-T associated cytokine release syndrome. Due to the observation that late stage COVID-19 lung inflammation may also represent a hyper-inflammation state, IL-6 inhibitors have been used for treatment of COVID-19 related acute respiratory distress syndrome (ARDS).

1. Tocilizumab is recommended for use in COVID-19 patients who have been admitted to the ICU and requiring HFNC, non-invasive mechanical ventilation, mechanical ventilations, or ECMO. Tocilizumab should be administered within the first 3-5 days from admission, ideally within 24 hours from admission to the ICU. Tocilizumab should be administered in combination with Dexamethasone (or a steroid equivalent to Dexamethasone 6 mg IV/PO).
2. Tocilizumab is recommended for use in COVID-19 patients, not in the ICU, who having increasing oxygen demands, while on Dexamethasone 6 mg IV/PO (or a steroid equivalent), and requiring HFNC or non-invasive mechanical ventilation, and with CRP of 75 mg/L. Tocilizumab should be administered within the first 3-5 days from admission.
3. Tocilizumab is not recommend for use in COVID-19 patients on room air.

What severity of COVID-19 would you recommend use of this medication?

Tocilizumab is an inpatient COVID-19 therapeutic and should not be used in the outpatient setting.

Tocilizumab should be used primarily in severe or critical illness as defined by the use of high-flow device, non-invasive ventilation, mechanical ventilation, or ECMO.

Considerations for use of Tocilizumab may be made in cases where there is progression from moderate disease to severe/critical disease.

Would you recommend restricting this medication in some way?

When able, Tocilizumab should be considered in consultation with Infectious Diseases. An Infectious Diseases consultation is not need in cases where the patient is admitted to the ICU.

Recommended dose:

• 8 mg/kg with a maximum dose of 800 mg x 1 dose to be used in combination with Dexamethasone or a steroid that is dose equivalent to 6 mg of Dexamethasone.
• A second dose may be considered in very few and select clinical circumstances (there is insufficient evidence to recommend the use of a second dose).

Recommended monitoring:

• No drug monitoring required

Availability:

• Yes, Tocilizumab is currently available to be use within our system. There are currently no shortages anticipated.

Special Considerations:

• Pregnant women: Tocilizumab is actively transported across the placenta, accumulating in the fetus, especially in the third trimester, and may affect the immune response of the fetus. Tocilizumab has been detected in very low concentrations in breast milk but has not been detected in the serum of breast-fed infants. It is unclear what effect Tocilizumab has on the gastrointestinal tract of breastfed infants. In RECOVERY, neither pregnancy nor breast feeding were an exclusion criteria for enrollment into the Tocilizumab arm of the study. The use of Tocilizumab at any trimester in pregnancy should be considered when clinically indicated, through a shared decision model, but without delaying therapy. Per the RECOVERY protocol - Parents should be advised that if “treated after 20 weeks’ gestation, their infant should not be immunized with live vaccines for the first 6 months of life. All non-live vaccinations are safe and should be undertaken.”
• Immunosuppressed: In immunosuppressed persons, Tocilizumab may be considered in consultation with Infectious Diseases.
• Kidney Disease: There is no contraindication for the use of Tocilizumab in kidney disease, including HD or CRRT.
• Liver Disease: Tocilizumab should be avoided in patients with ALT/AST >5x ULN, platelets count < 50,000, or high risk of gastrointestinal perforation. Tocilizumab may be considered in these cases with consultation from Infectious Diseases.

= Supporting use article

= Neutral Article

= Contradicting use article

Randomized Control Trials:

1. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19: a randomized, controlled, open-label, platform trial. (RECOVERY)
   • Study design: Randomized, controlled, open-label, platform trial [RCT SARS CoV-2]
   • Trial period: April 23, 2020 and January 24, 2021
   • Inclusion criteria:
     • SAR-CoV-2 positive
     • Within 21 days from enrollment
     • Hypoxia (SpO2 <92%) on room air or receipt of oxygen
     • CRP >/= 75 mg/L
   • Exclusion criteria:
     • Evidence of infection including TB or other bacterial, fungal, or viral infection
   • Intervention:
     • Tocilizumab 8mg/kg as a single infusion over 60 min
     • A second dose could be given 12-24 hours later, based on the opinion of the clinician
     • 82% received systemic corticosteroids
   • Placebo:
     • No placebo
     • Control population is standard of care
     • 82% received systemic corticosteroids
   • Sample Size:
     • 4116 adults randomized
     • 2022 allocated to Tocilizumab (1647 received Tocilizumab)
     • 2094 allocated to usual care alone (77 received Tocilizumab)
   • Primary outcome
     • All-cause mortality through 28 days
   • Secondary outcome:
     • Time to discharge from hospital
     • Receipt of mechanical ventilation/EMCO or death for those not on mechanical ventilation at the time of enrollment
     • Time t successful cessation of invasive mechanical ventilation
     • Use of renal dialysis or haemofiltration
   • Major Results:
     • The use of tocilizumab was associated with a significant reduction in 28-day mortality compared with usual care alone (31% in the tocilizumab group vs 35% in the usual care group; rate ratio 0·85; 95% CI, 0·76–0·94; p=0·0028).
     • The use of tocilizumab was associated with a greater probability of discharge from hospital within 28 days (57% vs 50%; rate ratio 1·22, 1·12–1·33, p <0.001).
     • Among those not on invasive mechanical ventilation at baseline, use of tocilizumab was associated with a reduction in the risk of progressing to invasive mechanical ventilation or death when compared with usual care alone (35% vs 42%, risk ratio 0·84, 0·77–0·92, p <0.0001).
   • EBM reviewer Conclusion: In hospitalized patients with hypoxia as defined by either use of supplemental oxygen, HFNC, non-invasive mechanical ventilation, mechanical ventilation or ECMO, and systemic inflammation (CRP >75 mg/L), the use of Tocilizumab led to a significant reduction in 28-day mortality, improved chances of being discharged alive from the hospital, and progression to invasive mechanical ventilation as compared to usual care. The benefits of Tocilizumab was seen in addition to the use of corticosteroids.
2. The REMAP-CAP Investigators. Interleukin-6 Receptor Antagonists in Critically Ill Patients with COVID-19. (REMAP-CAP)
   • Study design: Randomized, controlled, open-label, platform trial [RCT SARS CoV-2]
   • Trial period: April 19, 2020 and October 28, 2021
   • Inclusion criteria:
     • SAR-CoV-2 positive
     • Admitted to the ICU and receiving respiratory or cardiovascular organ support
   • Exclusion criteria:
     • >24 hours since admission to the ICU.
     • Immunosuppression
     • ALT>5 ULN
   • Intervention:
     • Tocilizumab 8mg/kg as a single infusion over 60 min
     • A second dose could be given 12-24 hours later, based on the opinion of the clinician
     • 93.9% received systemic corticosteroids within 48 hours of randomization
   • Placebo:
     • No placebo
     • Control population is standard of care
     • 92.7% received systemic corticosteroids within 48 hours of randomization
   • Sample Size:
     • 366 allocated to Tocilizumab (13 withdrew consent)
     • 412 allocated to usual care alone (10 withdrew consent)
   • Primary outcome:
     • Number of respiratory and cardiovascular organ support-free days up to day 21
   • Secondary outcome:
     • Time to discharge from hospital
     • Receipt of mechanical ventilation/EMCO or death for those not on mechanical ventilation at the time of enrollment
     • Time t successful cessation of invasive mechanical ventilation
     • Use of renal dialysis or haemofiltration
   • Major Results:
     • The median number of organ support–free days was 10 (interquartile range, −1 to 16) in the tocilizumab group and 0 (interquartile range, −1 to 15) in the control group
     • In-hospital mortality was 28.0% in the tocilizumab arm and 35.8% in the standard of care arm (aOR 1.64; 95% CrI, 1.14–2.35).
   • EBM reviewer Conclusion: Administration of Tocilizumab within 24 hours of ICU admission in COVID-19 patients who were on HFNC, non-invasive ventilation or mechanical ventilation had a significantly lower mortality and shorter duration of respiratory or cardiovascular organ support as compared to the standard of care group. This benefit was seen in combination with the use of corticosteroids.
3. Ivan O. Rosas, Norbert Brau, et al. Tocilizumab in Hospitalized Patients With Severe COVID-19 Pneumonia (COVACTA).
   • Study design: Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. [RCT SARS CoV-2]
   • Trial registry: ClinicalTrials.gov NCT04320615
   • Trial Period: April 3, 2020 – July 28, 2020
   • Inclusion criteria:
     • 18 years or older
     • Bilateral chest infiltrates on CXR or CT
     • SpO2
     • Exclusion criteria:
       • Allergy to TCZ
       • TB
       • Suspected active infection
       • Imminent death
       • Received oral anti-rejection or immunomodulatory drugs in the past three months
       • Pregnant or breastfeeding
       • ALT or AST >10x ULN
       • ANC
       • Platelet count
     • Intervention:
       • 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.
       • 36.1% received steroids
     • Placebo:
       • Placebo + standard of care
       • 54.9% received steroids
     • Sample Size:
       • mITT 294 patients randomized to tocilizumab and 144 to placebo
       • 224 of 301 patients (74.4%) randomized to tocilizumab and 108 of 151 patients (71.5%) randomized to placebo completed the 28-day follow-up
     • Primary Outcome:
       • Clinical status assessed on a 7-category ordinal scale at 28 days
     • Secondary Outcome:
       • Clinical status assessed on day 14 on a 7-category ordinal scale
       • Mortality at day 28
       • Ventilator-free days to day 28
     • Major Results:
       • Symptom onset median 11.0 (1.0 to 49.0) in tocilizumab and 10.0 (2.0 to 50.0) in placebo
       • Clinical status on the 7-category ordinal scale at day 28 was not statistically significantly improved for tocilizumab versus placebo (p=0.36).
       • There was no difference in the number of ventilator-free days with tocilizumab vs. placebo.
       • Median (95% CI) time to hospital discharge/ready for discharge was 20 days in the tocilizumab arm and 28 days in the placebo arm (log rank P=0.04; Cox proportional hazards ratio 1.35 [1.02 to 1.79]).
       • Median duration of ICU stay was 9.8 days in the tocilizumab arm and 15.5 days in the placebo arm (difference, –5.8 days [95% CI –15.0 to 2.9]; P=0.05).
     • Author Conclusion: There was no significant difference between tocilizumab and placebo in clinical status at day 28 as assessed using a 7-category ordinal scale. Tocilizumab potentially decreased time to hospital discharge, ready for discharge, duration of ICU stay, and in those not mechanically ventilated at the time of randomization, fewer treatment failures occurred in the tocilizumab group.
     • EBM Reviewer Conclusion: This study was not powered to detect mortality differences between treatment arms. The primary outcome of improvement in the 7-category ordinal scale at 28 days was not meet. Looking at secondary outcomes, there was a decrease in the time to hospital discharge, decrease duration in ICU stay, and in those who were not mechanically ventilated at the time of randomization, there was fewer patients who progressed to mechanical ventilation, ICU admission or death. There were more people in the placebo arm that received steroid vs. the tocilizumab arm. Median duration of symptoms at the time of randomization was 11 days in the tocilizumab arm vs 10 days in the placebo arm.
   • Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients Hospitalized with COVID-19 (BACC BAY). N Engl J Med. 2020 Oct 21.doi: 10.1056/NEJMoa2028836. Epub ahead of print.
     • Study design: Randomized, double-blind, placebo-controlled trial [RCT SARS CoV-2]
     • Trial registry: NCT04356937
     • Trial period: April 20 - June 15, 2020 at 7 Boston, Massachusetts hospitals
     • Inclusion criteria:
       • Hospitalized patients aged 19-85 years
       • SARS-CoV-2 infection confirmed by either nasopharyngeal swab PCR or serum IgM antibody assay
       • At least 2 of the following signs: fever (body temperature > 38 °C) within 72 hours before enrollment, pulmonary infiltrates, or a need for supplemental oxygen in order to maintain an oxygen saturation > 92%
       • At least 1 of the following lab criteria: CRP > 50 mg/L, ferritin > 500 ng/mL, D-dimer > 1,000 ng/mL, or lactate dehydrogenase > 250 U/L.
     • Exclusion criteria:
       • Receiving supplemental oxygen at a rate >10 L/min or mechanical ventilation
       • Patients between the ages of 79 and 86 with NYHA Class III/IV heart failure, insulin-dependent diabetes mellitus, angina, or treatment of a malignancy (excluding non- melanoma skin cancer) within six months
       • A recent history of treatment with biologic agents or small-molecule immunosuppressive therapy
       • Receiving other immunosuppressive therapy that the investigator believed placed them at higher risk for an infection
       • Uncontrolled bacterial, fungal, or non-COVID viral infection
       • History of diverticulitis or bowel perforation
       • ANC
       • AST/ALT > 5X ULN
       • Pregnancy
     • Intervention:
       • Tocilizumab IV (8 mg/kg, max 800 mg) a single dose
       • 11% received steroids
     • Standard care:
       • Some patients received remdesivir, hydroxychloroquine, and glucocorticoids as concomitant treatment; no patients received dexamethasone (RECOVERY trial results announced after this trial)
       • 6% received steroids
     • Sample size: N = 243 (control group: N = 81 (1 patient excluded from the modified intent-to-treat population who was intubated before receipt of placebo), treatment group: N = 161)
     • Primary outcome: Intubation or death, assessed in a time-to-event analysis (those event free censored at day 28)
     • Secondary outcome: Clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses (those event free censored at days 28 and 29, respectively)
     • Major results:
       • At day 28, 17 patients (10.6%) in the TCZ group and 10 patients (12.5%) in the placebo group had been intubated or had died (11 were intubated and 6 died without being intubated in the TCZ group; 8 were intubated and 2 died without being intubated in the placebo group)
       • The hazard ratio for intubation or death in the TCZ group as compared with the placebo group was 0.83 (95% CI, 0.38 - 1.81; P=0.64)
       • The hazard ratio for disease worsening was 1.11 (95% CI, 0.59 - 2.10; P=0.73) (Adjusted hazard ratio was 0.88 [95% CI, 0.45-1.72])
       • At 14 days, 18% of the TCZ group and 14.9% of the placebo group had worsening of disease; at 28 days, the percentages were 19.3% and 17.4%, respectively
       • The median time to discontinuation of supplemental oxygen was 5 days (IQR, 3.8 - 7.6) in the TCZ group and 4.9 days (IQR, 3.8 - 7.8) in the placebo group (P=0.69).
       • At 14 days, 24.6% of the TCZ group and 21.2% of the placebo group were still receiving supplemental oxygen; at 28 days, the percentages were 17.4% and 15.1%, respectively
       • Multivariate, adjusted models showed that patients older than 65 years of age were at greater risk for progression to intubation or death than younger patients
       • Patients who received TCZ had fewer serious infections than the placebo group (13 [8.1%] vs. 14 [17.3%]; P=0.03)
     • Author conclusion: TCZ was not effective for preventing intubation or death in moderately ill hospitalized patients with COVID-19
     • Funding: Genetech
     • EBM reviewer conclusion: Not supportive of TCZ use in moderately ill patients hospitalized with COVID-19 not mechanically ventilated or requiring > 10L supplemental oxygen; no significant effect on the risk of intubation or death, on disease worsening, on time to discontinuation of supplemental oxygen, or on any of the efficacy outcomes examined.
   • Salvarani C, Dolci G, Massari M, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. (RCT-TCZ-COVID-19 Study Group). JAMA Intern Med. 2020;e206615. doi:10.1001/jamainternmed.2020.6615. Online ahead of print.
     • Study design: A multicenter, open-label, randomized trial [RCT SARS CoV-2]
     • Trial registry: NCT04346355
     • Trial period: March 31 - June 11, 2020 at 24 Italian centers
     • Inclusion criteria:
       • Hospitalized patients 18 years and older
       • Diagnosis of COVID-19 confirmed by a positive SARS-CoV-2 RT-PCR assay in a respiratory tract specimen
       • PaO2/FiO2 ratio between 200 and 300 mg/Hg
       • An inflammatory phenotype defined by a temperature >38 °C during the last 2 days, and/or CRP >10 mg/dL and/or CRP increased to at least twice the admission measurement
     • Exclusion criteria:
       • ICU admission, not invasive or noninvasive mechanical ventilation
       • Receipt of IL-1 blocker, Jak inhibitor, or tumor necrosis factor medication(s); steroids were allowed if taken before hospitalization or if documented clinical worsening, then patients in either arm were eligible to receive any therapy, including steroids
       • Known hypersensitivity to tocilizumab
       • Any condition preventing future admission to ICU, such as advanced age with multiple comorbidities, as well as the patient's expressed will to avoid future intubation
       • Current documented bacterial infection
       • Pregnancy
     • Intervention: Tocilizumab IV (8 mg/kg up to max 800 mg) within 8 hours from randomization, followed by a second dose after 12 hours.
     • Sample size: N = 123 (control group: N=63; treatment group: N=60)
     • Primary outcome: Clinical worsening within 14 days since randomization, defined by the occurrence of 1 of the following: ICU admission with invasive mechanical ventilation, death from any cause, clinical aggravation documented by the finding of a PaO2/FiO2 ratio < 150 mmHg, whichever came first
     • Secondary outcome: The overall rate of patients admitted to the ICU with invasive mechanical ventilation and mortality at 14 and 30 days
     • Major results:
       • 28.3% (17/60 patients) in the TCZ group and 27% (17/63) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59 - 1.86; P=0.87)
       • All 34 episodes of clinical worsening occurred within 6 days after randomization, with no differences in time to the event between the 2 arms
       • 11 patients were admitted to ICU, all within 14 days since randomization, with no major differences between the 2 arms (10.0% vs 7.9%, respectively)
       • 2 patients in the TCZ group and 1 in the control group died before 30 days from randomization
       • Mortality at 14 days (1.7% vs 1.6%; rate ratio 1.05; 95% CI , 0.07-16.4) and at 30 days (3.3% vs 1.6%; rate ratio, 2.10; 95% CI, 0.20-22.6)
       • 6 patients in the TCZ group and 5 patients in the control group were intubated
       • There were 21 (17.1%) adverse events, 14 (23.3%) in the TCZ group and 7 (11.1%) in the standard care group; most common ADEs were increased ALT and decreased neutrophil count
       • The trial was prematurely interrupted after an interim analysis for futility
     • Author conclusion: TCZ did not reduce the risk of clinical worsening compared with placebo
     • Funding: partially funded by the Italian Ministry of Health; Roche provided the drug and its distribution to centers
     • EBM reviewer conclusion: Not supportive of tocilizumab use in hospitalized, non-ICU patients with COVID-19 pneumonia and a PaO2/FiO2 ratio between 200 and 300 mm Hg. Tocilizumab did not reduce the risk of clinical worsening. A blinded randomized trial (see above) also supports this conclusion.
   • Hermine O, Mariette X, Tharaux PL, et al. Effect of Tocilizumab vs Usual Care in Adults Hospitalized with COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. (CORIMUNO-TOCI-1). JAMA Intern Med. 2020 Oct 20;e206820. doi: 10.1001/jamainternmed.2020.6820. Online ahead of print.
     • Study design: Multicenter, open-label, randomized controlled trial [RCT SARS CoV-2]
       • Note: no placebo of TCZ was prepared due to emergency nature of the trial and feasibility issues
     • Trial registry: NCT04331808
     • Trial period: March 31 - April 18, 2020 at 9 French university hospitals
     • Inclusion criteria:
       • 18 years of age or older
       • CORIMUNO-19 cohort inclusion:
         • Confirmed SARS-CoV-2 infection (positive on rRT-PCR and/or typical chest CT scan)
         • Moderate, severe, or critical PNA (O2 > 3 L/min, WHO Clinical Progression Scale score >/= 5) [this study examines those with moderate or severe pneumonia; CORIMUNO-TOCI 2 is an ongoing trial conducted in patients with critical pneumonia]
       • CORIMUNO-TOCI-1 trial inclusion:
         • WHO-CPS score of 5
         • O2 levels >/= 3 L/min but without high-flow oxygen, noninvasive ventilation, or mechanical ventilation
     • Exclusion criteria:
       • Known hypersensitivity to tocilizumab or any of its excipients
       • Pregnancy
       • Current documented bacterial infection
       • Patients with one of the following lab results out of ranges detailed below at screening:
         • ANC
         • PLT < 50 G/L
     • Intervention: Tocilizumab (TCZ) plus usual care or usual care (UC) alone. TCZ IV 8 mg/kg on day 1. Additional fixed dose of TCZ 400 mg IV on day 3 was recommended if O2 requirement was not decreased by > 50% (decision left to treating physician). Usual care (antibiotic agents, antiviral agents, corticosteroids, vasopressor support, anticoagulants) was provided at the discretion of the clinicians.
     • Sample size: N=130 (control group: N=67; treatment group: N=63)
     • Primary outcome: 1) Proportion of patients dead or needing noninvasive or mechanical ventilation on day 4 (>5 on WHO-CPS) and 2) Survival with no need for noninvasive or mechanical ventilation at day 14
     • Secondary outcome: 1) Clinical status assessed with the WHO-CPS at day 7 and day 14, 2) overall survival, 3) time to discharge, 4) time to oxygen supply independency
     • Major results:
       • Antiviral drugs, glucocorticoids, and preventive or therapeutic anticoagulation were administered in 7 (11%), 21 (33%), and 59 (94%) patients, respectively, in the TCZ group, and 16 (24%), 41 (61%), and 61 (91%) in the UC group, respectively
       • On day 4, 12/63 (19%) in TCZ group and 19/67 (28%) in UC group had WHO-CPS score >5 (median posterior ARD, -9%; 90% CrI, -21 to 3)
       • On day 14, at least 1 event (NIV, HFO, MV, or death) had occurred in 15 patients in TCZ group (24%) and 24 pts in UC group (36%) (median posterior HR, 0.58; 90% CrI, 0.33-1.00)
       • 11/63 (17%) and 18/67 (27%) pts in TCZ and UC groups had MV or death at day 14 (posterior HR, 0.58; 90% CrI, 0.30-1.09)
         • On prespecified (for antiviral drugs) or post-hoc subgroup analyses (for corticosteroids, including dexamethasone), the effect of TCZ was numerically higher if combined with antiviral drugs (HR, 0.28; 90% CrI, 0.07-1.06) or corticosteroids (HR, 0.38; 90% CrI, 0.13-1.11)
       • Among patients who were not in ICU at randomization, 11/60 (18%) in the TCZ group and 22/64 (36%) in the UC group were subsequently admitted to the ICU (risk difference, 18%; 95% CI, 0.4-31%)
       • At day 28, 7 pts in TCZ group died and 8 pts in UC group died (adjusted HR, 0.92; 95% CI, 0.33-2.53)
       • Cumulative incidence of patients who had been weaned from oxygen at day 28 was 89% (95% CI, 78-95%) and 75% (95% CI, 62-83%) in the TCZ and UC group, respectively (HR, 1.41; 95% CI, 0.98-2.01)
       • Cumulative incidence of discharge by day 28 was 83% in TCZ and 73% in UC group (HR, 1.52; 95% CI, 1.02-2.27)
       • The number of serious adverse events was lower in the TCZ arm than UC group (27 vs 57) with a decreased incidence of serious bacterial infection (2 vs 11)
     • Author conclusion: No significant differences between SARS-CoV-2 positive patients with moderate to severe COVID-19 pneumonia who were neither admitted to an ICU nor required high-flow, NIV, or MV and who received TCZ and those who did not on WHO-CPS scores > 5 at day 4, but might have reduced the risk of NIV, MV, or death by day 14; no difference in 28-day mortality was found
     • Funding: publicly funded (Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research (FRM), AP-HP Foundation and the Reacting program)
     • EBM reviewer conclusion: Not supportive of tocilizumab use in hospitalized (non-ICU) patients with COVID-19 pneumonia. Of note, patients in the UC group received corticosteroids - and especially dexamethasone - twice as often as those in the TCZ group, potentially revealing some underlying bias given open label design. Further investigation is needed in this cohort with the small sample size and inconsistent use of dexamethasone. Overall, this study targeted a very small subset of hospitalized COVID-19 patients (WHO-CPS = 5 exactly and requiring at least 3 L/min O2), limiting generalizability.

Observational SARS CoV-2

1. Gupta S, Wang W, Hayek SS, et al. Association Between Early Treatment with Tocilizumab and Mortality Among Critically Ill Patients with COVID-19. JAMA Intern Med. 2020 Oct 20;e206252. doi:10.1001/jamainternmed.2020.6252. Online ahead of print.
   • Study design: Retrospective observational cohort study with adoption of a target trial emulation approach [Obs SARS CoV-2]
   • Trial Registry: Not listed
   • Trial period: March 4, 2020 to May 10, 2020 at 68 hospitals across the United States (data from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 [STOP-COVID])
   • Inclusion criteria:
     • At least 18 years of age
     • Laboratory-confirmed COVID-19 (detected by nasopharyngeal or oropharyngeal swab)
     • Admitted to an ICU for illness directly attributable to COVID-19
   • Exclusion criteria:
     • Enrollment in a placebo-controlled trial involving tocilizumab or other IL-6 antagonist
     • Hospitalization for 1 week or more before ICU admission
     • Liver dysfunction (AST or ALT > 500 U/L) on ICU admission
     • Receipt of an IL-6 antagonist other than tocilizumab during the first 2 days of ICU admission
     • Receipt of tocilizumab before ICU admission
   • Intervention: Patients were categorized according to whether they received or did not receive tocilizumab (either intravenously or subcutaneously) during the first 2 days of ICU admission; patients who received tocilizumab after the first 2 days of ICU admission were categorized in the non-tocilizumab-treated group; patients were followed until hospital discharge, death, or June 12, 2020 - whichever occurred first
   • Sample size: 3924 patients (433 [11%] were treated with tocilizumab within 2 days of ICU admission)
   • Primary outcome: In-hospital death
   • Secondary outcome: secondary infection (suspected or confirmed new infection other than COVID-19 developed after ICU admission), transaminitis (AST > 250 U/L, ALT > 500 U/L), arrhythmias (atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation), thrombotic complications (DVT, PE, stroke) occurring within 14 days after ICU admission
   • Major results:
     • Patients treated within 2 days of ICU admission with tocilizumab (n = 433) had a lower risk of death compared with those not treated with tocilizumab (n = 3,491) (hazard ratio [HR] 0.71, 95% CI 0.56-0.92)
       • 125 (28.9%) of patients treated with tocilizumab and 1,419 (40.6%) of patients not treated with tocilizumab died
       • The estimated 30-day mortality was 27.5% (95% CI 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%, 95% CI 3.1%-16.0%)
     • Tocilizumab-treated patients were younger, had fewer comorbidities, were more likely to have severe hypoxemia, and were more likely to receive corticosteroids on ICU admission
     • Tocilizumab-treated and non-tocilizumab–treated patients experienced the following adverse events: secondary infection (140 [32.3%] vs 1085 [31.1%]); AST or ALT level elevation of more than 250 U/L (72 [16.6%] vs 452 [12.9%]); AST or ALT elevation of more than 500 U/L (37 [8.5%] vs 196 [5.6%]); arrhythmias (63 [14.5%] vs 602 [17.2%]); and thrombotic complications (46 [10.6%] vs 342 [9.8%])
   • Author conclusion: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use tocilizumab
   • Funding: Several grants
   • EBM reviewer conclusion: The results are difficult to assess with no tocilizumab dosing and concurrent medication (e.g., antivirals, corticosteroids, etc.) information. Several factors may impact in-hospital death. With the time period of this study, inherent bias exists in the standard of care across several sites with the pandemic coming to fruition in the United States.
2. Malekzadeh R, Abedini A, Mohsenpour B, et al. Subcutaneous Tocilizumab in Adults with Severe and Critical COVID-19: A Prospective Open-label Uncontrolled Multicenter Trial. Int Immunopharmacol. 2020;89(Pt B):107102. doi:10.1016/j.intimp.2020.107102. Online ahead of print.
   • Study design: A prospective, open-label, uncontrolled, multicenter trial [Obs SARS CoV-2]
   • Trial registry: IRCT20150303021315N17
   • Trial period: March 15 - June 22, 2020 at 8 tertiary centers in Iran
   • Inclusion criteria:
     • All adult COVID-19 patients with confirmed diagnosis of SARS-CoV-2 infection either by PCR or by CT of the chest.
     • Fever defined as an oral temperature ≥ 37.8 °C
     • Cough, shortness of breath, or respiratory rate > 30 breaths/min that had SpO2 of 93% or less in room air
     • Serum IL-6 level > 3 times upper limit of normal or higher
   • Exclusion criteria:
     • Known hypersensitivity to tocilizumab or other component of the formulation
     • History of HBV, HCV, HIV, history of immunodeficiency, hepatic disorders, bone marrow suppression defined as ANC
   • Intervention: Tocilizumab subQ 324 mg ( < 100 kg body weight) or 486 mg (≥ 100 kg body weight) along with standard of care (SOC) treatment (supportive care, antiviral agents, hydroxychloroquine, subQ interferon beta-1a, and antibiotic agents)
   • Sample size: N = 126 (86 patients with severe disease and 40 patients with critical disease)
   • Primary outcome: All-cause mortality rate during the hospital stay
   • Secondary outcome: Changes in SpO2, body temperature, respiratory rate, lab values including CRP and WBC count from baseline through the last day of hospital stay
   • Major results:
     • The median (IOR) length of hospital stay from TCZ administration until discharge or death, was 8 days (5-12) in severe patients and 10 days (5.5-14) in critical patients.
     • By day 14, 4.65% (4/86) of severe patients and 50% (20/40) of critical patients died. By the end, 6.98% (6/86) of severe patients and 60% (24/40) of critical patients died. The risk of death was substantially greater among critical patients compared with severe patients (p < 0.001)
     • Outcomes concerning three additional endpoints (oral temperature, SpO2, and RR) were significantly improved as early as 3 days after TCZ administration in both groups, especially in severe patients
     • Significant improvement in the required level of oxygenation was reported in severe patients 7 days after TCZ administration
     • No TCZ-related serious adverse events occurred
     • Concluded subQ injection of TCZ might improve some clinical parameters and reduce the risk of death in COVID-19 patients, especially if in the early stages of respiratory failure.
   • Author conclusion: Observed significant improvements in some clinical parameters following subcutaneous administration of tocilizumab in hospitalized patients with severe or critical COVID-19 pneumonia. Data showed a modest trend in possible reduction in the risk of death, particularly if used in the early stages of respiratory failure.
   • Funding: AryoGen Co., Iran
   • EBM reviewer conclusion: The observational design along with subcutaneous tocilizumab administration (question variability of absorption amongst critically ill patients) are two key limitations. The data are supportive of subcutaneous tocilizumab use in this setting, but underlying bias exists, making generalizability difficult.
3. Rossi B, Nguyen LS, Zimmermann P, et al. Effect of Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia: A Case-Control Cohort Study. Pharmaceuticals (Basel). 2020;13(10):317. Published 2020 Oct 17. doi:10.3390/ph13100317
   • Study design: Observational single center retrospective cohort [Obs SARS CoV-2]
   • Trial registry: NCT04366206
   • Trial period: Began March 23, 2020, end date not reported at a primary care hospital in France
   • Inclusion criteria:
     • Severe COVID-19 pneumonia (SpO2 /= 6 L/min with oxygen mask for more than 6 hours)
     • Diagnosis required positive testing with RT-PCR or chest CT scan with typical lesions
   • Exclusion criteria:
     • Mechanical ventilation
     • Admission to the critical care medicine department
   • Intervention: Tocilizumab as a single IV 400 mg dose compared to those who did not receive tocilizumab
   • Sample size: N=246 (N=140 in control group, N=106 in tocilizumab group)
   • Primary outcome: Composite of all-cause mortality and invasive mechanical ventilation at 28 days
   • Secondary outcome: None
   • Major results:
     • In matched cohort, tocilizumab treatment associated with fewer events (HR=0.49, 95% CI 0.3-0.81, p=0.005)
     • Cox multivariable survival analysis found tocilizumab to be independently associated with lower incidence of primary outcome (adjHR=0.34, 95% CI 0.22-0.52, p <0.0001)
     • In the matched cohort, tocilizumab was associated with fewer deaths (HR=0.42, 95% CI 0.22-0.82, p=0.008)
     • In overall cohort, Cox multivariable analysis yielded independent protective association between tocilizumab and mortality (adjHR=0.29, 95% CI 0.17-0.53, p <0.0001)
   • Author conclusion: A single dose of tocilizumab 400 mg was associated with lower mortality and lesser need for mechanical ventilation
   • Funding: No external funding
   • EBM reviewer conclusions: These results do not replace the published randomized controlled trial data. Greater risk for residual confounding variables.
4. Price CC, Altice FL, Shyr Y, et al. Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes. Chest. 2020;158(4):1397-1408. doi:10.1016/j.chest.2020.06.006
   • Study design: Observational, retrospective [Obs SARS CoV-2]
   • Trial registry: None
   • Trial period: March 10 - April 21, 2020 at a single academic hospital in New Haven, Connecticut
   • Inclusion criteria:
     • Adults ≥ 18 years with a PCR-confirmed severe acute respiratory syndrome COVID-19
     • Patient who met criteria for severe disease, defined as receiving ≥ 3L of supplemental oxygen to maintain SpO2 > 93%; patients with critical disease (i.e., requiring mechanical ventilation)
     • Nonsevere patients with evolving CRS, manifested by increasing hs-CRP levels and oxygen requirements.
   • Exclusion criteria: Not stated
   • Intervention: Tocilizumab IV 8 mg/kg (not to exceed 800 mg); a second dose could be given if the patient had a markedly elevated BMI.
   • Sample size: N = 239 (N = 153 received tocilizumab group)
   • Primary outcome: 14-day survival
   • Secondary outcome: mechanical ventilation days and post-tocilizumab cytokine release syndrome (CRS) response
   • Major results:
     • Severe disease was associated with lower survival (78% vs 93%; P <0.001), greater portion requiring MV (44% vs 5%; P<0.001), and longer median mechanical ventilation days (5.5 vs 1; P=0.003)
     • TCZ-treated patients with severe disease had higher admission levels of hs-CRP (120 vs 71 mg/L; P <0.001) and received TCZ sooner (2 vs 3 days; P<0.001).
     • The survival rate was similar in severe and nonsevere disease groups (83% vs 91%; P=0.11).
     • For TCZ-treated patients requiring MV, survival rate was 75% (95% CI, 64-89).
     • Following TCZ treatment, oxygenation and inflammatory biomarkers (eg, hg-CRP, IL-6) improved, but D-dimer and soluble IL-2 receptor levels increased significantly.
     • Few adverse events were observed following TCZ treatment; 6 patients had post-treatment neutropenia and 4 patients had bacteremia > 10 days following TCZ administration. Increase in transaminases noticed.
   • Author conclusion: Tocilizumab may result in lower-than-expected mortality in a subgroup of patients with evidence of CRS; no causality established
   • Funding: No external funding
   • EBM reviewer conclusion: These results do not replace the published randomized controlled trial data. Significant concern for confounding variables with this trial design as severe patients were originally targeted followed by expansion to non-severe cases. This may be impacting the higher survival rates reported in comparison to already published literature.
5. Menzella F, Fontana M, Salvarani C, et al. Efficacy of Tocilizumab in Patients with COVID-19 ARDS undergoing Noninvasive Ventilation. Crit Care. 2020;24(1):589. Published 2020 Sep 29.doi:10.1186/s13054-020-03306-6
   • Study design: Retrospective case-control study [Obs SARS CoV-2]
   • Trial registry: None
   • Trial period: March 10 - May 18, 2020 at a single hospital in Italy
   • Inclusion criteria: Patients with SARS-CoV-2 infection confirmed by a positive RT-PCR assay for SARS-CoV-2 in a respiratory tract specimen and clinical and radiological findings compatible with COVID-19 severe pneumonia
   • Exclusion criteria: Not stated
   • Intervention:
     • Tocilizumab IV (8 mg/kg - max 800 mg) by two consecutive infusions 12h apart
     • Tocilizumab subQ ranging from 2 to 4 doses of 162 mg (administered simultaneously in a different injection site) per patient depending on drug availability and body weight.
     • Sample size: N = 79 (N = 41 in the treatment group; 28 patients with IV TCZ and 13 with subQ TCZ)
   • Primary outcome: In-hospital mortality rate
   • Secondary outcome: Outcome of worsening represented by the patients who died in the pulmonology unit or were intubated
   • Major results:
     • In-hospital overall mortality rate was 38% (30/79 patients). Regarding all TCZ treated patients, mortality rate was 24% (10/41), while was 18% (5/28) in the IV TCZ subgroup, 38% (5/13) in the SubQ TCZ group, and 53% (20/38) in the subgroup of patients not treated with TCZ
     • The probabilities of dying and being intubated during the follow-up were significantly lower in patients treated with TCZ compared to those not treated with TCZ (log-rank p value = 0.006 and 0.036, respectively)
     • Cox proportional hazards analyses adjusted by sex and age, patients treated with TCZ had a significantly reduced risk of intubation or death during the follow-up period (HR 0.44, 95% CI 0.22-0.89, p=0.022), while they did not have a reduced mortality (HR 0.55, 95%CI 0.22-1.35, p=0.192)
     • Among patients treated with TCZ, two developed cavitating lung lesions.
   • Author conclusion: TCZ treatment may be effective in COVID-19 patients with severe respiratory impairment receiving noninvasive ventilation
   • Funding: No external funding
   • EBM reviewer conclusion: The biggest limitations of this study are the retrospective nature and the small number of patients enrolled. Another limitation was that the TCZ route of administration was heterogeneous and there are no definitive data regarding similarities between intravenous and subcutaneous formulations. Prospective, randomized data is needed to further define tocilizumab use in COVID-19 patients.
6. Guillén L, Padilla S, Fernández M, et al. Preemptive Interleukin-6 blockade in Patients with COVID-19. Sci Rep. 2020;10(1):16826. Published 2020 Oct 8. doi:10.1038/s41598-020-74001-3
   • Study design: Observational cohort [Obs SARS CoV-2]
   • Trial registry: None
   • Trial period: March 10 - April 17, 2020 at a hospital in Spain
   • Inclusion criteria:
     • Confirmed or probable COVID-19
     • Initial SOFA score < 3
     • Exclusion criteria: Contraindications to use of tocilizumab in the study protocol included:
     • Neutrophil count < 500 x 10^9/L
     • AST/ALT > 5 x upper normal limit
     • Documented sepsis by other pathogens
   • Intervention:
     • Tocilizumab 600 mg if weight >/= 75 kg or 400 mg if weight < 75 kg
     • If no response after 24 hours, second dose of tocilizumab 400 mg (or IV steroids) was administered
   • Sample size: N=64 (no comparator group)
   • Primary outcome:
     • Response to therapy/favorable response (at least one of the following)
       • Resolution of fever
       • Improvement in tachypnea
       • Improvement in oxygen saturation by at least 5%
       • Decrease in CRP of at least 25%
       • No radiological progression 24 hours after tocilizumab administration
     • No response/unfavorable response (at least one of the following)
       • Absence of any of the 24 hour response criteria
       • Increase in SOFA score > 2 measured at 48-72 hours or at day 7 after tocilizumab
       • ICU admission
       • Death
   • Secondary outcome: Trends of inflammatory markers
   • Major results:
     • 49 (76.6%) patients had favorable and 15 (23.4%) had unfavorable response or adverse outcome (0 deaths)
     • Patients with favorable response to tocilizumab were younger, had fewer comorbidities, and were not as critically ill at the time of administration
   • Author conclusion: Patients admitted with COVID-19 in whom tocilizumab was used at an earlier stage of disease, there was a low rate of mortality
   • Funding: No external funding
   • EBM reviewer conclusion: Limitations of this study are the absence of a comparable control group and the possibility of selection bias in patients receiving tocilizumab due to the observational nature of the study. The small sample size also prompts the need for more prospective, randomized data.