Table 5c. Interleukin-6 Inhibitors: Selected Clinical Data

Last Updated: March 6, 2023

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 5c. Interleukin-6 Inhibitors: Selected Clinical Data
Methods	Results	Limitations and Interpretation
RECOVERY: Open-Label RCT of Tocilizumab and Usual Care in Hospitalized Adults With COVID-19 in the United Kingdom¹
Key Inclusion Criteria Evidence of COVID-19 progression ≤21 days after initial randomization to an intervention within the RECOVERY protocol, defined as: SpO₂ <92% on room air or receipt of supplemental oxygen; and CRP ≥75 mg/L Key Exclusion Criterion Presence of non-SARS-CoV-2 infection Interventions 1 weight-based dose of tocilizumab (maximum 800 mg) with possible second dose (n = 2,022) Usual care (n = 2,094) Primary Endpoint 28-day all-cause mortality Key Secondary Endpoints Time to discharge from hospital within 28 days Among those not on MV at baseline, death or receipt of MV (including ECMO) within 28 days	Participant Characteristics Mean age 64 years; 67% men; 76% White 95% with 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 28-day all-cause mortality: 31% in tocilizumab arm vs. 35% in usual care arm (rate ratio 0.85; 95% CI, 0.76–0.94; P = 0.003) 28-day all-cause mortality among those who required MV at baseline: 49% in tocilizumab arm vs. 51% in usual care arm (risk ratio 0.93; 95% CI, 0.74–1.18) Secondary Outcomes Proportion discharged from hospital within 28 days: 57% in tocilizumab arm vs. 50% in usual care arm (rate ratio 1.22; 95% CI, 1.12–1.33; P < 0.0001) Median time to hospital discharge: 19 days in tocilizumab arm vs. 28 days in usual care arm Proportion not on MV at baseline who died or required MV within 28 days: 35% in tocilizumab arm vs. 42% in usual care arm (rate ratio 0.84; 95% CI, 0.77–0.92; P < 0.0001)	Key Limitations Arbitrary CRP ≥75 mg/L cutoff for enrollment Difficult to define exact subset of patients in RECOVERY cohort who were subsequently selected for secondary randomization/tocilizumab trial Interpretation Among hospitalized patients with COVID-19, hypoxemia, and elevated CRP levels, the use of tocilizumab was associated with a reduction in all-cause mortality and a shorter time to hospital discharge.
REMAP-CAP: Open-Label, Adaptive-Platform RCT of Tocilizumab and Sarilumab in Adults With COVID-19 in 21 Countries in Europe and North America^2-4
Key Inclusion Criteria ICU admission Suspected or laboratory-confirmed SARS-CoV-2 infection Receipt of MV, NIV, or cardiovascular support Key Exclusion Criteria >24 hours after ICU admission Death imminent Immunosuppression ALT >5 times ULN Interventions SOC plus 1 of the following (drug selection based on provider preference, availability, or adaptive probability): 1 dose of tocilizumab 8 mg/kg IV with possible second dose in 12–24 hours (n = 952) Single dose of sarilumab 400 mg IV (n = 485) SOC alone (n = 406) Primary Endpoint Composite of in-hospital mortality and organ support-free days to Day 21, as measured by an OS Key Secondary Endpoints In-hospital survival All-cause mortality at 180 days	Participant Characteristics Mean age 60 years; 69% men; 75% White 86% with PCR-confirmed SARS-CoV-2 infection Median 14 hours between ICU admission and enrollment At baseline: 68% on HFNC oxygen or NIV 32% on MV On corticosteroids: 67% in SOC arm, 82% in tocilizumab arm, 89% in sarilumab arm Primary Outcomes Tocilizumab vs. SOC Median number of organ support-free days: 7 in tocilizumab arm vs. 0 in SOC arm Improved composite outcome, measured by an OS: median aOR 1.46 (95% CrI, 1.13–1.87) Highest CRP tercile: aOR 1.87 (95% CrI, 1.35–2.59) Outcomes consistent across subgroups according to oxygen requirement at baseline Sarilumab vs. SOC Median number of organ support-free days: 9 in sarilumab arm vs. 0 in SOC arm Improved composite outcome, measured by an OS: median aOR 1.50 (95% CrI, 1.13–2.00) Highest CRP tercile: aOR 1.85 (95% CrI, 1.24–2.69) Outcomes consistent across subgroups according to oxygen requirement at baseline Secondary Outcomes Tocilizumab vs. SOC In-hospital survival: 66% in tocilizumab arm vs. 63% in SOC arm (aOR 1.42; 95% CrI, 1.05–1.93) All-cause mortality at 180 days: 36% in tocilizumab arm vs. 40% in SOC arm (aHR 0.76; 95% CrI, 0.61–0.93) Sarilumab vs. SOC In-hospital survival: 67% in sarilumab arm vs. 63% in SOC arm (aOR 1.51; 95% CrI, 1.06–2.20) All-cause mortality at 180 days: 33% in sarilumab arm vs. 40% in SOC arm (aHR 0.72; 95% CrI, 0.56–0.91) Pooled Tocilizumab and Sarilumab Arms vs. SOC Arm All-cause mortality at 180 days: 35% in pooled arms vs. 40% in SOC arm (aHR 0.74; 95% CrI, 0.61–0.90)	Key Limitation The SOC arm closed in November 2020, after which patients were randomized to active arms only; enrollment in the tocilizumab and sarilumab arms was partially nonconcurrent with the SOC arm, and although comparisons to the 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 use of IL-6 receptor antagonists reduced all-cause mortality at 180 days. The treatment effect appeared to be strongest in the highest CRP tercile. Tocilizumab and sarilumab were similarly effective in these patients.
COVACTA: Double-Blind RCT of Tocilizumab in Hospitalized Adults With COVID-19 in 9 Countries in Europe and North America⁵
Key Inclusion Criteria PCR-confirmed SARS-CoV-2 infection Hypoxemia Bilateral chest infiltrates Key Exclusion Criteria Death imminent Presence of active non-SARS-CoV-2 infection Interventions 1 dose of tocilizumab 8 mg/kg with possible second dose, plus SOC (n = 294) Placebo plus SOC (n = 144) Primary Endpoint Clinical status at Day 28, as measured by an OS Key Secondary Endpoints Time to hospital discharge ICU LOS Mortality by Day 28	Participant Characteristics Mean age 61 years; 70% men; 58% White 30% on HFNC oxygen or NIV 38% on MV 25% with multiorgan failure Received corticosteroids at entry or during follow-up: 36% in tocilizumab arm vs. 55% in placebo arm Primary Outcome No significant difference between arms in clinical status at Day 28 (P = 0.31) Secondary Outcomes Median time to hospital discharge: 20 days in tocilizumab arm vs. 28 days in placebo arm (HR 1.35; 95% CI, 1.02–1.79) Median ICU LOS: 9.8 days in tocilizumab arm vs. 15.5 days in placebo arm (difference 5.8 days; 95% CI, –15.0 to 2.9) Mortality by Day 28: 20% in tocilizumab arm vs. 19% in placebo arm (P = 0.94)	Key Limitations Modest power to detect differences in Day 28 clinical status More patients received corticosteroids in placebo arm than tocilizumab arm. Interpretation There was no difference between the tocilizumab and placebo recipients in clinical status at Day 28 or survival. The median time to hospital discharge was significantly shorter in the tocilizumab arm than in the placebo arm. Although the result was not statistically significant, the tocilizumab arm had a shorter ICU LOS than the placebo arm.
EMPACTA: Double-Blind RCT of Tocilizumab in Hospitalized Adults With COVID-19 in 6 Countries in North America, South America, and Africa⁶
Key Inclusion Criteria PCR-confirmed SARS-CoV-2 infection COVID-19 pneumonia Key Exclusion Criteria Death imminent Receiving NIV or MV Interventions 1 dose of tocilizumab 8 mg/kg with possible second dose, plus SOC (n = 249) Placebo plus SOC (n = 128) Primary Endpoint Progression to MV, ECMO, or death by Day 28 Key Secondary Endpoints Time to hospital discharge or readiness for discharge, as measured by an OS 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: Corticosteroids: 80% in tocilizumab arm vs. 88% in placebo arm RDV: 53% in tocilizumab arm vs. 59% in placebo arm Primary Outcome Proportion who progressed to MV, ECMO, or death by Day 28: 12% in tocilizumab arm vs. 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: 6.0 days in tocilizumab arm vs. 7.5 days in placebo arm (HR 1.16; 95% CI, 0.91–1.48) All-cause mortality by Day 28: 10.4% in tocilizumab arm vs. 8.6% in placebo arm (95% CI, –5.2 to 7.8)	Key Limitation Moderate sample size Interpretation In patients with COVID-19 pneumonia, tocilizumab reduced the likelihood of progression to MV, ECMO, or death by Day 28 but did not reduce 28-day all-cause mortality.
BACC Bay: Double-Blind RCT of Tocilizumab in Hospitalized Adults With COVID-19 in the United States⁷
Key Inclusion Criteria Laboratory-confirmed SARS-CoV-2 infection ≥2 of the following conditions: Fever >38°C Pulmonary infiltrates Need for supplemental 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 Receipt of supplemental oxygen at rate >10 L/min Recent use of biologic agents or small-molecule immunosuppressive therapy Receipt of immunosuppressive therapy that increased risk for infection Interventions Tocilizumab 8 mg/kg plus usual care (n = 161) Placebo plus usual care (n = 81) Primary Endpoint Progression to MV or death by Day 28 Key Secondary Endpoints Clinical worsening by Day 28, as measured by an OS Discontinuation of supplemental oxygen among patients receiving it at baseline	Participant Characteristics Median age 60 years; 58% men; 45% Hispanic/Latinx, 43% White 50% with BMI ≥30; 49% with HTN; 31% with DM 80% receiving oxygen ≤6 L/min; 4% receiving HFNC oxygen; 16% receiving no supplemental oxygen Concomitant medications: Corticosteroids: 11% in tocilizumab arm vs. 6% in placebo arm RDV: 33% in tocilizumab arm vs. 29% in placebo arm Primary Outcome Progression to MV or death by Day 28: 11% in tocilizumab arm vs. 12% in placebo arm (HR 0.83; 95% CI, 0.38–1.81; P = 0.64) Secondary Outcomes Proportion with clinical worsening of disease by Day 28: 19% in tocilizumab arm vs. 17% in placebo arm (HR 1.11; 95% CI, 0.59–2.10; P = 0.73) Median time to discontinuation of oxygen: 5.0 days in tocilizumab arm vs. 4.9 days 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 Adults With Severe or Critical COVID-19 in 11 Countries in Europe, North America, South America, and Asia⁸
Key Inclusion Criteria COVID-19 pneumonia Requirement for supplemental oxygen or intensive care 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 OS Key Secondary Endpoint Survival to 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; 63% received ≥1 dose of corticosteroids during the study Primary Outcomes Median time to clinical improvement: 10 days in each sarilumab arm, 12 days in placebo arm Sarilumab 200 mg arm vs. placebo arm: HR 1.03; 95% CI, 0.75–1.40; P = 0.96 Sarilumab 400 mg arm vs. placebo arm: HR 1.14; 95% CI, 0.84–1.54; P = 0.34 Secondary Outcome Survival to Day 29: 92% in placebo arm; 90% in sarilumab 200 mg arm (P = 0.63 vs. placebo); 92% in sarilumab 400 mg arm (P = 0.85 vs. placebo)	Key Limitation Moderate sample size Interpretation Sarilumab did not reduce mortality or time to clinical improvement in hospitalized adults with COVID-19.
REMDACTA: Double-Blind RCT of Tocilizumab and Remdesivir in Hospitalized Patients With Severe COVID‑19 Pneumonia in Brazil, Russia, Spain, and the United States⁹
Key Inclusion Criteria Aged ≥12 years 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 Presence of non-SARS-CoV-2 infection Treatment with antivirals, CCP, CQ, HCQ, or JAK inhibitors Interventions Up to 10 days of 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 hospital discharge or readiness for discharge by Day 28 Key Secondary Endpoints: Time to MV or death by Day 28 Clinical status at Day 14, as measured by an OS Time to death by Day 28	Participant Characteristics Mean age 59 years, with 40% in tocilizumab arm and 34% in placebo arm aged ≥65 years; 63% men; 67% White Respiratory support: NIV or HFNC oxygen: 78% in tocilizumab arm vs. 83% in placebo arm MV or ECMO: 15% in tocilizumab arm vs. 11% in placebo arm Corticosteroid use: At baseline: 83% in tocilizumab arm vs. 86% in placebo arm During trial: 88% in each arm Primary Outcome Time to hospital discharge or readiness for discharge by Day 28: 14 days in each arm (HR 0.97; 95% CI, 0.78–1.19; P = 0.74) Secondary Outcomes No difference between arms in: Proportion who required MV or died by Day 28: 29% in each arm; time to death not evaluable (HR 0.98; 95% CI, 0.72–1.34; P = 0.90) Mean ordinal score for clinical status at Day 14: 2.8 in tocilizumab arm vs. 2.9 in placebo arm (P = 0.72) Proportion who died by Day 28: 18% in tocilizumab arm vs. 20% in placebo arm; time to death not evaluable (HR 0.95; 95% CI, 0.65–1.39; P = 0.79)	Key Limitations During the trial, primary outcome changed from clinical status at Day 28 to time to hospital discharge or readiness for discharge by 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 readiness for discharge in patients with severe COVID-19 pneumonia. There was no difference in mortality between the arms.
Key: ALT = alanine transaminase; AST = aspartate transaminase; BMI = body mass index; CCP = COVID-19 convalescent plasma; CQ = chloroquine; CRP = C-reactive protein; CT = computed tomography; CXR = chest X-ray; DM = diabetes mellitus; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate; HCQ = hydroxychloroquine; HFNC = high-flow nasal cannula; HTN = hypertension; ICU = intensive care unit; IL = interleukin; IV = intravenous; JAK = Janus kinase; LDH = lactate dehydrogenase; LOS = length of stay; MV = mechanical ventilation; NIV = noninvasive ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; RCT = randomized controlled trial; RDV = remdesivir; SOC = standard of care; SpO₂ = oxygen saturation; ULN = upper limit of normal

References

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.
REMAP-CAP Investigators. 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.
REMAP-CAP Investigators. 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.
Writing Committee for the REMAP-CAP Investigators. Long-term (180-day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial. JAMA. 2023;329(1):39-51. Available at: https://pubmed.ncbi.nlm.nih.gov/36525245/.
Rosas IO, Bräu 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.
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.
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.
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.
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.