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

Last Updated: December 16, 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 4e. 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 within 28 days
  • Among those not on MV at enrollment, receipt of MV or death within 28 days

Participant Characteristics:

  • Mean age 63.6 years; 67% men; 76% White
  • 95% had PCR-confirmed SARS-CoV-2 infection
  • At baseline:
    • 45% on conventional oxygen
    • 41% on HFNC oxygen or NIV
    • 14% on MV
    • 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 MV 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 than usual care arm (57% vs. 50%; rate ratio 1.22; 95% CI, 1.12–1.33; P < 0.0001).
  • Proportion of patients not on MV at baseline who died or required MV within 28 days 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 COVID-19 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 MV, NIV, 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 IV and possible second dose in 12–24 hours, 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 ordinal endpoint of in-hospital mortality and organ support-free days to Day 21

Key Secondary Endpoint:

  • In-hospital survival

Participant Characteristics:

  • Mean age 60 years; 69% men; 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 oxygen or NIV
    • 33% on MV
    • 67% on corticosteroids in SOC 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 according to oxygen requirement at baseline.

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 according to 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 (ordinal score)

Key Secondary Endpoints:

  • Time to discharge
  • ICU LOS
  • Day 28 mortality

Participant Characteristics:

  • Mean age 61 years; 70% men; 58% White
  • 30% on HFNC oxygen or NIV
  • 14% on MV
  • 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 LOS 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 arm).

Key Limitations:

  • Modest power to detect differences in Day 28 clinical status
  • More patients in placebo arm than tocilizumab arm received corticosteroids
  • Few patients on MV

Interpretation:

  • There was no difference between arms in Day 28 clinical status or survival.
  • The median times for recovery and ICU LOS were shorter in the tocilizumab arm than in the 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:

  • NIV or MV

Interventions:

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

Primary Endpoint:

  • MV, ECMO, or death by Day 28

Key Secondary Endpoints:

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

Participant Characteristics:

  • Mean age 56 years; 59% men; 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 MV or ECMO or 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).

Secondary Outcomes:

  • Median time to hospital discharge or readiness for discharge was 6.0 days in 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 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 MV, ECMO, or death by Day 28 but provided no benefit for 28-day all-cause 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

Key Exclusion Criteria:

  • Requiring supplemental oxygen at rate >10 L/min
  • Recent use of biologic agents or small molecule immunosuppressive therapy that investigators believe place the patient at a higher risk for infection

Interventions:

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

Primary Endpoint:

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

Key Secondary Endpoints:

  • Clinical worsening by Day 28 (ordinal score)
  • Discontinuation of supplemental oxygen among patients receiving it at baseline

Participant Characteristics:

  • Median age 60 years; 58% men; 45% Hispanic/Latinx
  • 50% with BMI ≥30; 49% with HTN; 31% with DM
  • 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 rate of Day 28 MV 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).

Secondary Outcomes:

  • No difference between arms in proportion of patients who had 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 MV 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:

  • 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% men; 77% White; 36% Hispanic/Latinx
  • 39% on HFNC oxygen, MV, or NIV
  • 42% with BMI ≥30; 43% with HTN; 26% with type 2 DM
  • 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).

Secondary Outcome:

  • No difference among the arms in survival rate 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.
REMDACTA: Double-Blind RCT of Tocilizumab and Remdesivir in Hospitalized Patients With Severe COVID‑19 Pneumonia8

Key Inclusion Criteria:

  • PCR-confirmed SARS-CoV-2 infection
  • Hospitalized with pneumonia confirmed by CXR or CT and requiring supplemental oxygen >6 L/min

Key Exclusion Criteria:

  • eGFR <30 mL/min
  • ALT or AST >5 times ULN
  • Infection other than SARS-CoV-2
  • Treatment with antivirals, CP, CQ, HCQ, JAK inhibitors

Interventions:

  • Up to 10 days RDV plus:
  • Tocilizumab 8 mg/kg IV, with second dose within 8–24 hours if indicated (n = 434)
  • Placebo (n = 215)

Primary Endpoint:

  • Time to discharge or “ready for discharge” through Day 28

Key Secondary Endpoints:

  • Time to MV or death through Day 28
  • Day 14 clinical status (ordinal score)
  • Time to death through Day 28

Participant Characteristics:

  • Mean age 59 years; 40% in tocilizumab arm and 34% in placebo arm aged ≥65 years
  • 63% men; 67% White
  • Respiratory support:
    • 78% in tocilizumab arm and 83% in placebo arm on NIV or high-flow oxygen
    • 15% in tocilizumab arm and 11% in placebo arm required MV or ECMO
  • Corticosteroid use:
    • 83% in tocilizumab arm and 86% in placebo arm at baseline
    • 88% in each arm during the trial

Primary Outcome:

  • No difference between arms in time to discharge or “ready for discharge” through Day 28 (14 days in each arm; HR 0.97; 95% CI, 0.78–1.19; P = 0.74).

Secondary Outcomes:

  • There was no difference between the arms in key secondary outcomes:
    • Proportion of patients in each arm who required MV or died by Day 28 was 29%; time to death was non-evaluable (HR 0.98; 95% CI, 0.72–1.34; P = 0.90).
    • Mean ordinal score for clinical status at Day 14 was 2.8 in tocilizumab arm and 2.9 in placebo arm (P = 0.72).
    • 18% of patients in tocilizumab arm and 20% in placebo arm died by Day 28; time to death was non-evaluable (HR 0.95; 95% CI, 0.65–1.39; P = 0.79).

Key Limitations:

  • During the trial, primary outcome changed from clinical status on Day 28 to time to discharge or “ready for discharge” to Day 28
  • Imbalances in patient characteristics at baseline between arms
  • Possible underrepresentation of patients with rapidly progressive disease

Interpretation:

  • Compared with placebo plus RDV, tocilizumab plus RDV did not shorten the time to discharge or “ready for discharge” in patients with severe COVID-19 pneumonia.
  • There was no difference in mortality between the arms.

References

  1. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33933206.
  2. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. 2021;384(16):1491-1502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631065.
  3. The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.06.18.21259133v2.
  4. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med. 2021;384(16):1503-1516. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33631066.
  5. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;384(1):20-30. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33332779.
  6. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med. 2020;383(24):2333-2344. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33085857.
  7. Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, Phase 3 trial. Lancet Respir Med. 2021;9(5):522-532. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33676590.
  8. Rosas IO, Diaz G, Gottlieb RL, et al. Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial. Intensive Care Med. 2021;47(11):1258-1270. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34609549.