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

Last Updated: October 19, 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 4d. Interleukin-6 Inhibitors: Selected Clinical Data
Methods Results Limitations and Interpretation
RECOVERY Trial: Open-Label RCT of Tocilizumab and Usual Care in Hospitalized Patients With COVID-191
Key Inclusion Criteria:
  • SpO2 <92% on room air or receipt of supplemental oxygen
  • CRP ≥75 mg/L

Key Exclusion Criteria:

  • Non-SARS-CoV-2 infection

Interventions:

  • Single weight-based dose of tocilizumab (maximum 800 mg) and possible second dose (n = 2,022)
  • Usual care (n = 2,094)

Primary Endpoint:

  • 28-day all-cause mortality

Key Secondary Endpoints:

  • Time to discharge alive
  • Among those not on IMV at enrollment, receipt of IMV or death

Participant Characteristics:

  • Mean age 63.6 years; 67% male; 76% White
  • 95% had PCR-confirmed SARS-CoV-2 infection
  • At baseline:
    • 45% on conventional oxygen
    • 41% on HFNC or noninvasive ventilation
    • 14% on IMV
    • 82% on corticosteroids

Primary Outcomes:

  • Day 28 mortality was lower in tocilizumab arm than in usual care arm (31% vs. 35%; rate ratio 0.85; 95% CI, 0.76–0.94; P = 0.003).
  • Among those who required IMV at baseline, Day 28 mortality was similar between arms (49% in tocilizumab arm vs. 51% in usual care arm; risk ratio 0.93; 95% CI, 0.74–1.18).

Secondary Outcomes:

  • Proportion of patients discharged alive within 28 days was greater in tocilizumab arm (57% vs. 50%; rate ratio 1.22; 95% CI, 1.12–1.33; P < 0.0001).
  • Among those not on IMV at baseline, the percentage of patients who died or required IMV was lower in tocilizumab arm than usual care arm (35% vs. 42%; rate ratio 0.84; 95% CI, 0.77–0.92; P < 0.0001).
Key Limitations:
  • Arbitrary enrollment cut off at CRP ≥75 mg/L
  • Difficult to define exact subset of patients in RECOVERY cohort who were subsequently selected for secondary randomization/tocilizumab trial

Interpretation:

  • Among hospitalized patients with hypoxemia and elevated CRP, tocilizumab was associated with reduced all-cause mortality and shorter time to discharge.
REMAP-CAP: Open-Label, Adaptive Platform RCT of Tocilizumab and Sarilumab in Patients With COVID-192,3
Key Inclusion Criteria:
  • ICU admission
  • Suspected or laboratory-confirmed COVID-19
  • Receipt of IMV, noninvasive ventilation, or cardiovascular support

Key Exclusion Criteria:

  • >24 hours since ICU admission
  • Presumption of imminent death
  • Immunosuppression
  • ALT >5 times ULN

Interventions:

  • Single dose of tocilizumab 8 mg/kg and possible second dose, plus SOC (n = 952)
  • Single dose of sarilumab 400 mg IV plus SOC (n = 485)
  • SOC (n = 406)

Randomization:

  • Adaptative randomization. Patients were randomized to receive SOC only, SOC plus tocilizumab, or SOC plus sarilumab based on provider preference, availability, or adaptive probability. SOC arm was closed in November 2020 (n = 366 for tocilizumab, n = 48 for sarilumab, n = 412 for SOC).
  • After November 2020, patients were randomized mostly to receive tocilizumab, sarilumab, or anakinra until April 10, 2021.

Primary Endpoint:

  • Composite endpoint measured using an ordinal scale that combined mortality and days free of respiratory or cardiovascular support to Day 21

Key Secondary Endpoint:

  • In-hospital survival

Participant Characteristics:

  • Mean age 60 years; 69% male; 75% White
  • 86% had PCR-confirmed SARS-CoV-2 infection
  • Median time from ICU admission until enrollment was 14 hours
  • At baseline:
    • 67% on HFNC or noninvasive ventilation
    • 33% on IMV
    • 67% on corticosteroids in control arm, 82% in tocilizumab arm, and 89% in sarilumab arm

Primary Outcomes

Tocilizumab Versus SOC:
  • Median number of organ support-free days was 7 in tocilizumab arm and 0 in SOC arm.
  • Median adjusted OR for ordinal scale was 1.46 (95% CrI, 1.13–1.87).
  • In highest CRP tercile, aOR was 1.87 (95% CrI, 1.35–2.59).
  • Outcomes were consistent across subgroups of oxygen requirements at study entry.
Sarilumab Versus SOC:
  • Median number of organ support-free days was 9 in sarilumab arm and 0 in SOC arm.
  • Median adjusted OR for ordinal scale was 1.50 (95% CrI, 1.13–2.00).
  • In highest CRP tercile, aOR was 1.85 (95% CrI, 1.24–2.69).
  • Outcomes were consistent across subgroups of oxygen requirements at study entry.

Secondary Outcomes

Tocilizumab Versus SOC:
  • In-hospital survival was 66% in tocilizumab arm and 63% in SOC arm (aOR 1.42; 95% CrI, 1.05–1.93).
Sarilumab Versus SOC:
  • In-hospital survival was 67% in sarilumab arm and 63% in SOC arm (aOR 1.51; 95% CrI, 1.06–2.20).
Key Limitation:
  • Enrollment in tocilizumab and sarilumab arms was partially nonconcurrent with SOC arm; while the comparisons to SOC arm were adjusted for time period, there is a possibility of bias

Interpretation:

  • Among patients with respiratory failure who were within 24 hours of ICU admission, the tocilizumab and sarilumab arms had higher rates of in-hospital survival and shorter durations of organ support than the SOC arm.
  • The treatment effect appeared to be strongest in the highest CRP tercile.
  • Tocilizumab and sarilumab were similarly effective, with a 99% probability of noninferiority of sarilumab.
COVACTA: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-194
Key Inclusion Criteria:
  • PCR-confirmed SARS-CoV-2 infection
  • Hypoxemia
  • Bilateral chest infiltrates

Key Exclusion Criteria:

  • Death imminent
  • Active infection other than SARS-CoV-2

Interventions:

  • Single dose of tocilizumab 8 mg/kg and possible second dose, plus SOC (n = 294)
  • Placebo plus SOC (n = 144)

Primary Endpoint:

  • Day 28 clinical status (measured using ordinal scale)

Key Secondary Endpoints:

  • Time to discharge
  • Length of ICU stay
  • Day 28 mortality

Participant Characteristics:

  • Mean age 61 years; 70% male; 58% White
  • 30% on HFNC or noninvasive ventilation
  • 14% on IMV
  • 25% with multiorgan failure
  • 36% in tocilizumab arm and 55% in placebo arm received corticosteroids at entry or during follow-up

Primary Outcome:

  • No significant difference between arms in clinical status at Day 28.

Secondary Outcomes:

  • Shorter median time to discharge in tocilizumab arm than placebo arm (20 vs. 28 days; HR 1.35; 95% CI, 1.02–1.79).
  • Shorter median ICU stay in tocilizumab arm than placebo arm (9.8 vs. 15.5 days).
  • No difference in Day 28 mortality between arms (19.7% in tocilizumab arm vs. 19.4% placebo).
Key Limitations:
  • Modest power to detect differences in Day 28 clinical status
  • Corticosteroids used by more patients in placebo arm than tocilizumab arm
  • Few patients on IMV

Interpretation:

  • There was no difference between arms at Day 28 clinical status or survival.
  • Patients in tocilizumab arm had shorter median times for recovery and ICU stay than those in placebo arm.
EMPACTA: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-195
Key Inclusion Criteria:
  • PCR-confirmed SARS-CoV-2 infection
  • COVID-19 pneumonia

Key Exclusion Criteria:

  • Noninvasive ventilation or IMV

Interventions:

  • Single dose of tocilizumab 8 mg/kg plus SOC, possible second dose (n = 249)
  • Placebo plus SOC (n = 128)

Primary Endpoint:

  • IMV, ECMO, or death by Day 28

Key Secondary Endpoints:

  • Time to hospital discharge or readiness for discharge (measured using ordinal scale)
  • All-cause mortality by Day 28

Participant Characteristics:

  • Mean age 56 years; 59% male; 56% Hispanic/Latinx, 15% Black/African American, 13% American Indian/Alaska Native
  • 84% with elevated CRP
  • Concomitant medications:
    • 80% on corticosteroids and 53% on RDV in tocilizumab arm
    • 88% on corticosteroids and 59% on RDV in placebo arm

Primary Outcome:

  • Proportion of patients who required IMV or ECMO or who died by Day 28 was 12% in tocilizumab arm and 19% in placebo arm (HR 0.56; 95% CI, 0.33–0.97; P = 0.04).

Key Secondary Outcomes:

  • Median number of days to hospital discharge or readiness for discharge was 6.0 in tocilizumab arm and 7.5 in placebo arm (HR 1.16; 95% CI, 0.91–1.48).
  • All-cause mortality by Day 28 was not statistically different between arms (10.4% in tocilizumab arm vs. 8.6% in placebo arm).
Key Limitation:
  • Moderate sample size

Interpretation:

  • Among patients with COVID-19 pneumonia, tocilizumab lowered rates of IMV, ECMO, or death by Day 28 but provided no benefit for 28-day mortality.
BACC Bay: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-196
Key Inclusion Criteria:
  • Laboratory-confirmed SARS-CoV-2 infection
  • ≥2 of the following conditions:
    • Fever >38°C
    • Pulmonary infiltrates
    • Need for oxygen
  • ≥1 of the following laboratory criteria:
    • CRP ≥50 mg/L
    • D-dimer >1,000 ng/mL
    • LDH ≥250 U/L
    • Ferritin >500 ng/mL

Interventions:

  • Tocilizumab 8 mg/kg plus usual care (n = 161)
  • Placebo plus usual care (n = 81)

Primary Endpoint:

  • Intubation or death, according to a time to event analysis; data censored at Day 28

Key Secondary Endpoints:

  • Clinical worsening by Day 28, based on an ordinal scale
  • Discontinuation of supplemental oxygen among patients receiving it at baseline

Participant Characteristics:

  • Median age 60 years; 58% male; 45% Hispanic/Latinx
  • 50% with BMI ≥30; 49% with HTN; 31% with diabetes
  • 80% receiving oxygen ≤6 L/min; 4% receiving high-flow oxygen; 16% receiving no supplemental oxygen
  • Concomitant medications:
    • 11% on corticosteroids and 33% on RDV in tocilizumab arm
    • 6% on glucocorticoids and 29% on RDV in placebo arm

Primary Outcome:

  • No difference between arms in Day 28 intubation or death (10.6% in tocilizumab arm vs. 12.5% in placebo arm; HR 0.83; 95% CI, 0.38–1.81; P = 0.64).

Key Secondary Outcomes:

  • No difference between arms in proportion of patients who experienced worsening of disease by Day 28 (19% in tocilizumab arm vs. 17% in placebo arm; HR 1.11; 95% CI, 0.59–2.10).
  • Median number of days to discontinuation of oxygen was 5.0 in tocilizumab arm and 4.9 in placebo arm (P = 0.69).
Key Limitations:
  • Wide confidence intervals due to small sample size and low event rates
  • Few patients received RDV or corticosteroids

Interpretation:

  • There was no benefit of tocilizumab in preventing intubation or death, reducing the risk of clinical worsening, or reducing the time to discontinuation of oxygen. This could be due to the low rate of concomitant corticosteroid use among the study participants.
Double-Blind, RCT of Sarilumab in Hospitalized Patients With Severe or Critical COVID-197
Key Inclusion Criteria:
  • Aged ≥18 years
  • Severe or critical laboratory-confirmed COVID-19
  • COVID-19 pneumonia

Key Exclusion Criteria:

  • Low probability of surviving or remaining at study site
  • Dysfunction of ≥2 organ systems and need for ECMO or renal replacement therapy

Interventions:

  • Sarilumab 400 mg IV (n = 173)
  • Sarilumab 200 mg IV (n = 159)
  • Placebo (n = 84)
Primary Endpoint:
  • Time to clinical improvement of ≥2 points on a 7-point scale
Key Secondary Endpoint:
  • Survival at Day 29

Participant Characteristics:

  • Median age 59 years; 63% male; 77% White; 36% Hispanic/Latinx
  • 39% on HFNC, IMV, or noninvasive mechanical ventilation
  • 42% with BMI ≥30; 43% with HTN; 26% with type 2 diabetes
  • 20% received systemic corticosteroids before receiving intervention

Primary Outcome:

  • No difference in median time to clinical improvement among the sarilumab arms (10 days for each) and placebo arm (12 days).

Key Secondary Outcome:

  • No difference among the arms in survival at Day 29 (92% in placebo arm vs. 90% in sarilumab 200 mg arm vs. 92% in sarilumab 400 mg arm).
Key Limitations:
  • Only 20% of patients received corticosteroids
  • Moderate sample size and a small placebo arm

Interpretation:

  • There was no benefit of sarilumab in hospitalized adults with COVID-19 in time to clinical improvement or mortality. This could be due to the low rate of concomitant corticosteroid use among the study participants.