Table 4b. Interleukin-6 Inhibitors: Selected Clinical Data

Last Updated: April 21, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for IL-6 inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations..

Table 4b. Interleukin-6 Inhibitors: Selected Clinical Data
Study Design Methods Results Limitations and Interpretation
Tocilizumab in Hospitalized Patients With COVID-19 (RECOVERY Trial)1
Second randomization of the RECOVERY trial, an open-label, randomized controlled-platform trial assessing several treatments in hospitalized patients with COVID-19 in the United Kingdom (n = 4,116; 19% of all RECOVERY trial participants [n = 21,550]) Key Inclusion Criteria:
  • Suspected or laboratory-confirmed COVID-19
  • Participant within 21 days of enrollment into the initial randomization of the RECOVERY trial
  • Hypoxia evidenced by SpO2 <92% on room air or receipt of supplemental oxygen
  • CRP ≥75 mg/L

Key Exclusion Criteria:

  • Tocilizumab unavailable at participating hospital
  • Evidence of active non-SARS-CoV-2 infection, including TB or other bacterial, fungal, or viral infection

Interventions

1:1 Randomization:

  • Single dose of tocilizumab 8 mg/kg, and possible second dose, or
  • Usual care

Primary Endpoint:

  • All-cause mortality through 28 days

Secondary Endpoint:

  • Time to discharge alive
  • Among those not on mechanical ventilation at enrollment, receipt of mechanical ventilation or death
Number of Participants:
  • Tocilizumab (n = 2,022) and usual care (n = 2,094)
  • Recruitment period: April 14, 2020, through January 24, 2021

Participant Characteristics:

  • Mean age was 63.6 years.
  • 67% of participants were men.
  • 68% of participants were white.
  • 94% of participants had PCR-confirmed SARS-CoV-2 infection.
  • Median time from hospitalization until enrollment was 2 days (IQR 1–5 days).
  • Median CRP 143 mg/L (IQR 107–204 mg/L).
  • At baseline, 45% of participants were on conventional oxygen, 41% on HFNC/noninvasive ventilation, and 14% on mechanical ventilation.
  • At enrollment, 82% of participants were taking corticosteroids.

Primary Outcomes:

  • Mortality by Day 28 was lower in the tocilizumab arm than in the usual care arm (29% vs. 33%; rate ratio 0.86; 95% CI, 0.77–0.96).
  • Subgroup analysis: Among those who required mechanical ventilation at baseline, mortality by Day 28 was similar in the tocilizumab and usual care arms (47% vs. 48%).

Secondary Outcomes:

  • The proportion of patients who were discharged alive within 28 days was greater in tocilizumab arm than usual care arm (54% vs. 47%; rate ratio 1.22; 95% CI, 1.12–1.34).
  • Among those not on mechanical ventilation at baseline, the percentage of participants who met the secondary outcome of mechanical ventilation or death was lower in the tocilizumab arm than in the usual care arm (33% vs. 38%; risk ratio 0.85; 95% CI, 0.78–0.93).
Limitations:
  • Open-label study
  • Limited collection of AEs
  • Only a small proportion of the participants were from ethnic or racial minority groups.
  • Difficult to define exact subset of hospitalized patients in full RECOVERY cohort who were subsequently selected for secondary randomization/tocilizumab trial.
  • Arbitrary cut off of CRP ≥75 mg/L

Interpretation:

  • Among hospitalized patients with severe or critical COVID-19 with hypoxia and elevated CRP levels (≥75 mg/L), tocilizumab was associated with reduced all-cause mortality and shorter time to discharge.
Interleukin-6 Receptor Antagonists in Critically Ill Patients With COVID-19–Preliminary Report (REMAP-CAP)2

Multinational RCT in critically ill, hospitalized patients with COVID-19 (n = 865)

Key Inclusion Criteria:
  • Suspected or laboratory-confirmed COVID-19
  • Admitted to ICU and receiving respiratory or cardiovascular organ support

Key Exclusion Criteria:

  • >24 hours since admission to ICU
  • Presumption of imminent death with lack of commitment to full support
  • Immunosuppression
  • ALT >5 times ULN

Interventions

1:1 Randomization:

  • Single dose of tocilizumab 8 mg/kg, and possible second dose, plus SOC, or
  • SOC

Alternative 1:1:1 Randomization:

  • Single dose of tocilizumab 8 mg/kg, and possible second dose, plus SOC, or
  • Single dose of sarilumab 400 mg IV plus SOC, or
  • SOC

Primary Endpoint:

  • Composite endpoint measured on an ordinal scale combining in-hospital mortality (assigned value: -1) and days free of respiratory or cardiovascular organ support up to Day 21
Number of Participants:
  • Tocilizumab plus SOC (n = 353), sarilumab plus SOC (n = 48), and SOC (n = 402)
  • Recruitment period: April 19 through October 28, 2020

Participant Characteristics:

  • Mean age was 61.4 years.
  • 73% of participants were men.
  • 72% of participants were White.
  • 84.4% of participants had a positive SARS-CoV-2 PCR test.
  • Median time from hospitalization until enrollment: 1.2 days (IQR 0.8–2.8 days).
  • Median time from ICU admission until enrollment: 13.6 hours (IQR 6.6–19.4 hours).
  • Baseline level of oxygen support: 28.8% of participants on HFNC, 41.5% on noninvasive ventilation, 29.4% on mechanical ventilation.
  • In mITT analysis, majority of patients (719 of 792 [90%]) received corticosteroids.

Primary Outcomes:

  • Median number of organ support-free days was 10 (IQR -1 to 16 days), 11 (IQR 0–16 days), and 0 (IQR -1 to 15 days) for the tocilizumab, sarilumab, and SOC arms, respectively.
  • Adjusted OR 1.64 (95% CrI, 1.25–2.14) for tocilizumab arm vs. SOC arm
  • In-hospital mortality: 28.0% for patients receiving tocilizumab and 35.8% for patients receiving SOC (aOR 1.64; 95% CrI, 1.14–2.35).
  • Percentage of patients who were not mechanically ventilated who progressed to intubation or death: 41.3% in tocilizumab arm vs. 52.7% in SOC arm.
Limitations:
  • Open-label study
  • Very few patients randomized to receive sarilumab.
  • Limited collection of AEs
  • Low proportion of participants from ethnic/racial minority populations

Interpretation:

  • Among the patients with severe/critical COVID-19 who were on high-flow oxygen or noninvasive ventilation or who were mechanically ventilated and within 24 hours of ICU admission, the tocilizumab arm had lower mortality and shorter duration of organ support. This benefit of tocilizumab may be in conjunction with concomitant corticosteroids given the high rate of corticosteroid use among trial participants.
  • REMAP-CAP enrolled patients within 24 hours of ICU level care who were undergoing rapid progression of respiratory dysfunction, a key difference to other tocilizumab trials.
Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia (COVACTA)3

Multinational, double-blind, placebo-controlled randomized trial in hospitalized patients with COVID-19 (n = 452)

Key Inclusion Criteria:
  • COVID-19 confirmed by positive PCR test
  • Severe COVID-19 pneumonia evidenced by hypoxemia and bilateral chest infiltrates

Key Exclusion Criteria:

  • Death imminent within 24 hours
  • Active TB or bacterial, fungal, or viral infection (other than SARS-CoV-2)

Interventions

2:1 Randomization:

  • Single dose of tocilizumab 8 mg/kg, and possible second dose, plus SOC
  • Placebo plus SOC

Primary Endpoint:

  • Clinical status at Day 28 (as measured on a 7-category ordinal scale)

Secondary Endpoints:

  • Time to discharge
  • Length of ICU stay
  • Mortality at Day 28

Ordinal Scale Categories:

  1. Discharged or ready for discharge
  2. Hospitalized on medical ward, not on supplemental oxygen
  3. Hospitalized on medical ward, on supplemental oxygen
  4. On oxygen by HFNC or noninvasive ventilation
  5. On mechanical ventilation
  6. Multiorgan failure (with ECMO or mechanical ventilation plus other support)
  7. Death
Number of Participants:
  • mITT analysis: tocilizumab (n = 294) and placebo (n = 144)

Participant Characteristics:

  • Mean age was 61 years.
  • 70% of participants were men.
  • 58% of participants were White.
  • Median time from symptom onset to randomization: 11 days
  • Clinical status at baseline by ordinal scale category: 28% of participants on supplemental oxygen (category 3); 30% on HFNC/noninvasive ventilation (category 4); 14% on mechanical ventilation (category 5); and 25% with multiorgan failure (category 6).
  • Percentage of participants who received corticosteroids at entry or during follow-up: 36% in tocilizumab arm vs. 55% in placebo arm.

Primary Outcome:

  • There was no significant difference in clinical status on 7-category ordinal scale on Day 28 between the arms: median of category 1 for the tocilizumab arm vs. category 2 for the placebo arm (difference -1.0; 95% CI, -2.5 to 0.0; P = 0.31).

Secondary Outcomes:

  • The time to discharge was shorter in the tocilizumab arm than in the placebo arm (median of 20 days vs. 28 days; HR 1.35; 95% CI, 1.02–1.79).
  • ICU stays were shorter in the tocilizumab arm than in the placebo arm (median of 9.8 days vs. 15.5 days; difference of 5.8 days; 95% CI, -15.0 to -2.9).
  • There was no difference in mortality by Day 28 between the arms (19.7% in tocilizumab arm vs. 19.4% in placebo arm; 95% CI, -7.6 to 8.2; P = 0.94).
  • SAEs occurred in 34.9% of patients in the tocilizumab arm vs. 38.5% in the placebo arm.
Limitations:
  • Modest power to detect differences in clinical status on Day 28 (the primary outcome) between the study arms
  • Corticosteroids only used by a subset of patients, which included more patients from the placebo arm; RDV use was rare.
  • Results mostly generalizable to the sickest patients with COVID-19.

Interpretation:

  • There was no difference between tocilizumab and placebo for clinical status (including death) at Day 28 (the primary outcome), but tocilizumab did demonstrate a shorter time to recovery and shorter length of ICU stay (secondary outcomes).
Effect of Tocilizumab on Clinical Outcomes at 15 Days in Patients With Severe or Critical COVID-2019 (TOCIBRAS)4
RCT in severe or critically ill hospitalized patients with COVID-19 in Brazil (n = 129) Key Inclusion Criteria:
  • COVID-19 confirmed by PCR test and radiographic imaging
  • Receiving oxygen to maintain SpO2 >93% or mechanical ventilation for <24 hours

Key Exclusion Criteria:

  • Active, uncontrolled infection
  • Elevated AST or ALT >5 times ULN
  • Reduced renal function with eGFR <30 mL/min/1.72 m2

Interventions:

  • Single dose of tocilizumab 8 mg/kg plus SOC
  • SOC

Primary Endpoints:

  • Clinical status at 15 days by ordinal scale category.
  • Following the statistical analysis plan, the primary outcome for the final analysis was changed to mechanical ventilation or death at Day 15 (categories 6 and 7), because the assumption of proportional odds was not met for the original 7-category ordinal outcome.

Key Secondary Endpoint:

  • All-cause mortality to Day 28

Ordinal Scale Categories:

  1. Not hospitalized, no limitation in activities
  2. Not hospitalized, limitation in activities
  3. Hospitalized, not receiving supplemental oxygen
  4. Hospitalized, receiving supplemental oxygen
  5. Hospitalized, receiving NIPPV or high-flow oxygen through a nasal cannula
  6. Hospitalized, receiving mechanical ventilation
  7. Death
Number of Participants:
  • Tocilizumab (n = 65) and SOC (n = 64)

Participant Characteristics:

  • Mean age was 57 years.
  • 68% of participants were men.
  • Mean time from symptom onset to randomization: 10 days
  • Baseline level of oxygen support: 52% of participants on conventional oxygen, 32% on HFNC or noninvasive ventilation, and 16% on mechanical ventilation.
  • 86% of participants received corticosteroids.
  • No patient received RDV, which was unavailable in Brazil during the study period.

Primary Outcomes:

  • There was no evidence for a treatment difference in the primary outcome: 28% of participants in the tocilizumab arm vs. 20% in the SOC arm had died or received mechanical ventilation at Day 15 (OR 1.54; 95% CI, 0.66–3.66; P = 0.32).
  • The study was stopped early by recommendation of the Data Monitoring Committee because of increased risk of death in the tocilizumab group: by Day 15, 16.9% of participants in the tocilizumab arm vs. 3.1% in SOC arm had died (OR 6.42; 95% CI, 1.59–43.2).

Key Secondary Outcomes:

  • Tocilizumab was associated with a trend towards increased mortality at Day 28 (21% in tocilizumab arm vs. 9% in SOC arm; OR 2.70; 95% CI, 0.97–8.35).
  • AEs were reported in 43% of patients in the tocilizumab arm and 34% in the SOC arm.
Limitations:
  • Open-label study
  • Relatively small sample size
  • Study was stopped early during the first interim review because of increased risk of death at Day 15.

Interpretation:

  • In this study population, tocilizumab demonstrated no benefit with respect to mechanical ventilation or death at Day 15 or key secondary outcomes.
  • There were more deaths at Day 15 in the tocilizumab arm than in the SOC arm.
Tocilizumab in Nonventilated Patients Hospitalized With COVID-19 Pneumonia (EMPACTA)5
Multinational, double-blind, placebo-controlled, Phase 3 randomized trial in hospitalized patients with COVID-19 (n = 389) Key Inclusion Criteria:
  • COVID-19 confirmed by PCR test and radiographic imaging
  • Severe COVID-19 pneumonia

Key Exclusion Criteria:

  • Receipt of noninvasive ventilation or mechanical ventilation

Interventions

2:1 Randomization:

  • Single dose of tocilizumab 8 mg/kg plus SOC, possible second dose if not improving, or
  • Placebo plus SOC

Primary Endpoint:

  • Mechanical ventilation or death by Day 28

Key Secondary Endpoints:

  • Time to hospital discharge or readiness for discharge
  • All-cause mortality by Day 28
Number of Participants:
  • mITT analysis: Tocilizumab (n = 249) and placebo (n = 128)

Participant Characteristics:

  • Mean age was 55.9 years.
  • 59.2% of participants were men.
  • 56.0% of participants were Hispanic/Latinx, 14.9% were Black/African American, and 12.7% were American Indian/Alaska Native.
  • 81% of participants were enrolled at sites in the United States.
  • Median time from symptom onset to randomization was 8 days.
  • Percentage of participants who received concomitant medications:
    • Tocilizumab arm: 80.3% received corticosteroids (55.4% received dexamethasone) and 52.6% received RDV
    • Placebo arm: 87.5% received corticosteroids (67.2% received dexamethasone) and 58.6% received RDV

Primary Outcome:

  • By mITT analysis, the cumulative proportion of patients who required mechanical ventilation or who had died by Day 28 was 12.0% in the tocilizumab arm and 19.3% in the placebo arm (HR 0.56; 95% CI, 0.33–0.97; P = 0.04)

Key Secondary Outcomes:

  • The median time to hospital discharge or readiness for discharge was 6.0 days in the tocilizumab arm and 7.5 days in placebo arm (HR 1.16; 95% CI, 0.91–1.48).
  • All-cause mortality by Day 28 was 10.4% (95% CI, 7.2% to 14.9%) in the tocilizumab arm and 8.6% (95% CI, 4.9% to 14.7%) in the placebo arm.
  • SAEs were reported in 15.2% of patients in the tocilizumab arm and 19.7% in the placebo arm.
Limitation:
  • Interaction with steroids not explored

Interpretation:

  • Among patients with severe COVID-19, tocilizumab lowered rates of mechanical ventilation or death by Day 28 but provided no benefit in 28-day mortality.
Efficacy of Tocilizumab in Patients Hospitalized With COVID-19 (BACC Bay Tocilizumab Trial)6
Double-blind, placebo-controlled randomized trial in hospitalized patients with COVID-19 in the United States (n = 243) Key Inclusion Criteria:
  • Hospitalized with COVID-19 confirmed by a positive PCR or serum IgM test
  • Moderate and severe COVID-19 with >2 of the following symptoms: fever >38°C, pulmonary infiltrates, need for oxygen to maintain saturation >92% and also 1 of the following: CRP ≥50 mg/L, D-dimer >1,000 ng/mL, LDH ≥250 U/L, ferritin >500 ng/mL

Interventions

2:1 Randomization:

  • Tocilizumab 8 mg/kg once plus usual care; or
  • Placebo plus usual care
Primary Endpoint:
  • Time to intubation or death (if the patient died without intubation)
Key Secondary Endpoints:
  • Clinical worsening
  • Discontinuation of supplemental oxygen among patients receiving it at baseline
Number of Participants
  • mITT analysis: Tocilizumab (n = 161) and placebo (n = 81)

Participant Characteristics:

  • Median age was 59.8 years (range 21.7–85.4 years).
  • 58% of participants were men.
  • 45% of participants were Hispanic or Latinx.
  • 50% of participants had BMI ≥30; 49% had HTN, and 31% had diabetes.
  • 80% of participants were hospitalized in non-ICU wards and receiving supplemental oxygen ≤6 L/min; 4% received high-flow oxygen; 16% required no supplemental oxygen.
  • Median time from symptom onset to randomization was 9 days.
  • Percentage of participants receiving concomitant medications:
    • Glucocorticoids: 11% in tocilizumab arm vs. 6% in placebo arm
    • RDV: 33% in tocilizumab arm vs. 29% in placebo arm.

Primary Outcomes:

  • There was no evidence of a treatment difference (i.e., time to intubation or death) between tocilizumab and placebo (HR 0.83; 95% CI, 0.38–1.81; P = 0.64).
  • By Day 28, 11% of the patients in the tocilizumab arm vs. 13% in the placebo arm had been intubated or had died.

Key Secondary Outcomes:

  • By Day 28, 19% of patients in the tocilizumab arm vs. 17% in the placebo arm had experienced worsening of disease (HR 1.11; 95% CI, 0.59–2.10).
  • The median time to discontinuation of oxygen was 5.0 days in the tocilizumab arm vs. 4.9 days in placebo arm (P = 0.69).
  • Fewer serious infections occurred among participants in the tocilizumab arm than in the placebo arm (8.1% vs. 17.3%; P = 0.03).
Limitations:
  • The relatively small sample size and low event rates resulted in wide confidence intervals for primary and secondary outcomes.
  • Some patients received RDV, and a few patients received steroids.

Interpretation:

  • In this study population, tocilizumab provided no benefit in preventing intubation or death (the primary outcome) or reducing the risk of clinical worsening or time to discontinuation of supplemental oxygen (secondary outcomes).
Effect of Tocilizumab Versus Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia (CORIMUNO-TOCI-1)7
Open-label, randomized clinical trial in hospitalized patients with COVID-19 in France (n = 131) Key Inclusion Criteria:
  • COVID-19 confirmed by positive PCR test and/or findings/abnormalities typical of COVID-19 on chest CT
  • Severe disease/pneumonia, requiring ≥3 L oxygen

Key Exclusion Criteria:

  • Receipt of high-flow oxygen or mechanical ventilation

Interventions

1:1 Randomization:

  • Single dose of tocilizumab 8 mg/kg on Day 1, possible second, fixed dose of tocilizumab 400 mg on Day 3 per provider if oxygen requirement not decreased by >50%, plus usual care, or
  • Usual care
Primary Endpoints:
  • Scores >5 on the 10-point WHO Clinical Progression Scale on Day 4
  • Survival without need of ventilation (including noninvasive ventilation) at Day 14
Key Secondary Endpoint:
  • Overall survival by Day 28
Number of Participants:
  • ITT analysis (n = 130): Tocilizumab (n = 63) and placebo (n = 67)

Participant Characteristics:

  • Median age was 64 years.
  • 68% of the participants were men.
  • Diagnosis of COVID-19 was confirmed by PCR test in 90% of participants.
  • Median time from symptom onset to randomization: 10 days
  • Baseline corticosteroids use was balanced (received by approximately 17% of participants in each arm) at randomization, but post randomization, more participants received corticosteroids in the control group (55%) than in the tocilizumab group (30%).

Primary Outcome:

  • In the Bayesian analyses, evidence for the superiority of tocilizumab vs. usual care did not reach the prespecified threshold for the proportion of patients who died or needed high-flow oxygen, noninvasive ventilation, or IMV by Day 4 (19% of patients in tocilizumab arm vs. 28% in usual care arm), but did reach the threshold by Day 14 (24% of patients in tocilizumab arm vs. 36% in usual care arm (HR 0.58; 90% CrI, 0.33–1.00).

Secondary Outcomes:

  • There was no difference in overall survival by Day 28 between tocilizumab arm and usual care arm (89% vs. 88%; adjusted HR 0.92; 95% CI, 0.33–2.53).
  • SAEs occurred in 20 patients (32%) in the tocilizumab arm and 29 patients (43%) in the usual care arm (P = 0.21).
  • There were fewer serious bacterial infections in the tocilizumab arm (2) than in the usual care arm (11).
Limitations:
  • Not blinded
  • Underpowered
  • More patients received dexamethasone/corticosteroids in the usual care arm.

Interpretation:

  • Among patients with severe COVID-19, tocilizumab led to improved ventilator-free survival at Day 14 suggesting possible benefit, but the clinical implications are unclear as there was no difference in survival for tocilizumab vs. usual care through Day 28.
Effect of Tocilizumab Versus Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia (RCT-TCZ-C19)8
Open-label RCT in hospitalized patients with COVID-19 in Italy (n = 126) Key Inclusion Criteria:
  • COVID-19 pneumonia confirmed by positive PCR test
  • Acute respiratory failure (i.e., PaO2/FiO2 200–300 mm Hg), fever, and/or a CRP ≥10 mg/dL and/or CRP level increased to at least twice admission value

Key Exclusion Criteria:

  • Advanced age, multiple comorbidities, or any other condition precluding ICU-level care

Interventions

1:1 Randomization:

  • 2 doses of tocilizumab 8 mg/kg (maximum of 800 mg, second dose after 12 hours), or
  • Usual care
Primary Endpoints:
  • Composite outcome defined as entry into ICU with IMV, death from all-causes, or clinical aggravation (PaO2/FiO2 <150 mm Hg) within 14 days
Key Secondary Endpoint:
  • Mortality at 30 days
Number of Participants:
  • ITT analysis (n = 123): Tocilizumab (n = 60) and usual care (n = 63)

Participant Characteristics:

  • Median age was 60 years.
  • 61% of participants were men.
  • Participants in usual care arm had lower CRP, IL-6, ferritin, and D-dimer levels and received more antivirals than participants in tocilizumab arm.

Primary Outcome:

  • No difference in the composite primary outcome of entry into ICU with mechanical ventilation, all-cause death, or clinical deterioration (PaO2/FiO2 <150 mm Hg) within 14 days: Met by 17 participants (28.3%) in tocilizumab arm vs. 17 (27.0%) in usual care arm (rate ratio 1.05; 95% CI, 0.59–1.86; P = 0.87)
    • ICU admissions: 10.0% of participants in tocilizumab arm vs. 7.9% in usual care arm (rate ratio 1.26; 95% CI, 0.41–3.91)
    • Mortality at 14 days: 1.7% in tocilizumab arm vs. 1.6% in usual care arm (rate ratio 1.05; 95% CI, 0.07–16.4)

Key Secondary Outcomes:

  • There was no difference in mortality at 30 days between tocilizumab arm (3.3%) and usual care arm (1.6%; rate ratio 2.10; 95% CI, 0.20–22.6).
  • There were more AEs among the participants in tocilizumab arm (23.3%) than among those in usual care arm (11.1%). The reported AEs were mostly elevated ALT levels and reduced neutrophil counts.
Limitations:
  • Not blinded
  • Small sample size
  • Mortality rate in the study population was significantly lower (2.4%) than in the general population in Italy (13.2%).9
  • Because 14 patients in the control group (22%) received tocilizumab after they reached the primary endpoint, mortality outcomes are difficult to interpret.
  • There were some differences between the arms in baseline participant characteristics, including higher inflammatory markers in the tocilizumab arm.

Interpretation:

  • This study demonstrated no evidence for a benefit of tocilizumab in patients hospitalized with COVID-19 pneumonia.
Sarilumab in Hospitalized Patients With Severe or Critical COVID-1910
Multinational double-blind, placebo-controlled, Phase 3 randomized trial in patients hospitalized with COVID-19 (n = 420) Key Inclusion Criteria:
  • Aged ≥18 years
  • Laboratory-confirmed COVID-19 and clinical or radiographic evidence of pneumonia
  • Severe or critical disease (i.e., receiving supplemental oxygen, including delivery by nasal cannula or high-flow device, noninvasive ventilation or invasive ventilation, or treatment in ICU)

Key Exclusion Criteria:

  • Low probability of surviving or remaining at investigational site beyond 48 hours
  • Dysfunction of ≥2 organ systems, or need for ECMO or renal replacement therapy at screening

Interventions

2:2:1 Randomization:

  • Sarilumab IV 400 mg, or
  • Sarilumab IV 200 mg, or
  • Placebo
Primary Endpoints:
  • Time from baseline to ≥2-point improvement in clinical status on a 7-point ordinal scale
Key Secondary Endpoint:
  • Proportion of patients alive at Day 29
Number of Participants:
  • mITT analysis (n = 416): Sarilumab 400 mg (n = 173), sarilumab 200 mg (n = 159), and placebo (n = 84)

Participant Characteristics:

  • Median age was 59 years.
  • 63% of participants were men.
  • 77% of participants were White and 36% were Hispanic or Latino.
  • 42% of participants had BMI ≥30.
  • 43% of participants had HTN and 26% had type 2 diabetes.
  • 61% of participants had severe disease and 39% had critical disease.
  • 20% of participants received systemic corticosteroids before receiving their assigned intervention.

Primary Outcome:

  • There was no difference in the median time to ≥2-point improvement in clinical status from baseline on the 7-point ordinal scale for either dose of sarilumab compared to placebo:
    • 12 days for placebo vs. 10 days for sarilumab 200 mg (HR 1.03; 95% CI, 0.75–1.40) and 10 days for sarilumab 400 mg (HR 1.14; 95% CI, 0.84–1.54).

Key Secondary Outcome:

  • There was no difference among the arms in proportion of patients who were alive at Day 29 (92% in placebo arm, 90% in sarilumab 200 mg arm, 92% in sarilumab 400 mg arm).
Limitations:
  • Low rate of baseline corticosteroid use and varying rate of overall corticosteroid use during the study
  • Moderate sample size with few participants in placebo arm

Interpretation:

  • In hospitalized adults with severe or critical COVID-19, there was no benefit of sarilumab with respect to time to clinical improvement or mortality.
Tocilizumab Plus Standard Care Versus Standard Care in Patients With Moderate to Severe COVID-19-Associated Cytokine Release Syndrome (COVINTOC)11
Open-label, Phase 3 RCT in patients hospitalized with moderate to severe COVID-19 cytokine release syndrome in India Key Inclusion Criteria:
  • Aged ≥18 years
  • SARS-CoV-2 infection confirmed by PCR test
  • Moderate disease (defined by respiratory rate 15–30 breaths/min, SpO2 90% to 94%) to severe disease (defined by respiratory rate ≥30 breaths/min, SpO2 <90% on ambient air, ARDS, or septic shock)

Key Exclusion Criteria:

  • Low probability of surviving beyond 24 hours
  • Receipt of immunomodulatory drugs within previous 6 months
  • Serious medical conditions per judgment of investigators

Interventions

1:1 Randomization:

  • Tocilizumab 6 mg/kg (maximum dose 480 mg), second dose allowable if no improvement or worsening of clinical symptoms in next 7 days, or
  • Usual care
Primary Endpoint:
  • Proportion of patients with progression from moderate to severe disease or from severe disease to death by Day 14
Key Secondary Endpoints:
  • Incidence of mechanical ventilation
  • Ventilator-free days
Number of Participants:
  • mITT analysis (n = 179): Tocilizumab (n = 91) and usual care (n = 88)

Participant Characteristics:

  • Median age was 55 years.
  • 85% of participants were men.
  • The mean BMI was 27.
  • Approximately 40% of participants had HTN and 41% had type 2 diabetes.
  • In the tocilizumab arm, 45% of participants had moderate disease and 55% had severe disease. In the usual care arm, 53% of participants had moderate disease and 47% had severe disease.
  • 91% of participants received systemic corticosteroids during the study.

Primary Outcome:

  • Overall, the percentage of patients with disease progression was 12.1% in tocilizumab arm and 18.2% in usual care arm.

Key Secondary Outcomes:

  • There was no observed difference between the arms in incidence of mechanical ventilation or number of ventilator-free days.
  • In post hoc analysis, the percentage of patients who had progressed from severe COVID-19 to death was 16% in tocilizumab arm and 34% in usual care arm (P = 0.04).
Limitations:
  • Open-label study
  • Underpowered
  • Lower dose of tocilizumab than in other trials

Interpretation:

  • There was no demonstrated benefit of tocilizumab in hospitalized adults with moderate to severe COVID-19.