INTRODUCTION
STRUCTURE AND GENERAL FUNCTION OF IL-6
1 The hexamer of IL-6 band structure (DOI: 10.2210/pdb1IL6/pdb) (left), and hexamer (IL-6/IL-6R/gp130) (DOI: 10.2210/pdb1P9M/pdb) (right) |
THE ROLE OF IL-6 IN CYTOKINE STORM DURING COVID-19 PATHOGENESIS
Cytokine storm in COVID-19 pathogenesis
IL-6 in cytokine storm of COVID-19
INHIBITORS OF IL-6
1 List of clinical trials on monoclonal antibodies against IL-6 or IL-6R for COVID-19 |
Drug | Participants | Location | Design | Inclusion criteria | Primary outcome measures | NCT/Reference |
a CRP: C-reactive protein. b Interstitial pneumonia requiring admission and at least two of the following: 1. Fever ≥ 37.8 °C (tympanic); 2. IL-6 in serum ≥ 25 ng/mL (in the absence of a previous dose of prednisone or equivalent > 1 mg/kg) or PCR > 5 mg/dL; 3. Lymphocytes < 600 mm 3; 4. Ferritin > 300 mcg/L that doubles in 24 h; 5. Ferritin > 600 mcg/L in the first determination and LDH > 250 U/L; 6. D-dimer (> 1 mg/L). c The patients with illness of any duration, with evidence of pneumonia, and severe disease as defined by at least one of the following: 1. High oxygen requirements (face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula); 2. Lymphocytes < 0.8 × 10 9 L−1; 3. Serum ferritin > 300 ng/mL; 4. Increased levels of D-dimer (> 1500 ng/mL) or D-dimer progressively increasing (over three consecutive measurements) and reaching ≥1000 ng/mL; 5. CPR > 10 mg/dL, or increasing over 24 h. d Having either of the following COVID-associated respiratory syndromes: 1. Pneumonia with oxygenation parameters SpO2 ≤ 93% (on room air) or respiratory rate greater than 30 min−1; 2. ARDS ( PaO2/FiO2 ≤ 300 mmHg or SpO2/FiO2 ≤ 315 if PaO2 is not available. | ||||||
TCZ | 450 | Global | A randomized, double-blind, placebo-controlled, multicenter study | Confirmed patients, SpO2 ≤ 93% or PaO2/FiO2 < 300 mmHg | Clinical status as per the 7-category ordinal scale at day 28 | 04320615/ Hoffmann-La Roche 2020 |
TCZ | 500 | Spain | A multicenter, open-label study | Confirmed severe/critical patients, ≤2 days of TCZ or its candidate | To calculate the time of intubation, oxygen therapy, non-invasive mechanical ventilation and mortality rate | 04445272/ Fundacion SEIMC-GESIDA 2020 |
TCZ | 332 | US | A multicenter, randomized, controlled phase 2 study | Confirmed adults with fever (T ≥ 38 °C) | Time to recovery (time frame: 28 days) | 04479358/ University of Chicago 2020a |
TCZ | 310 | Malaysia | An open-label, randomized, cross-over interventional study | Symptomatic patients with progressive disease and cytokine storm (presence of clinical and radiological signs) | The proportion and mean days of mechanical ventilation (time frame: average of 6 months) | 04345445/ University of Malaya 2020 |
TCZ | 400 | Naples | A multicenter, single-arm, open-label, phase 2 study | Confirmed patients, oxygen saturation at rest in ambient air ≤93% or requiring oxygen therapy or mechanical ventilation | Mortality (within 2 weeks / 1 month) | 04317092/National Cancer Institute 2020 |
TCZ | 32 | US | A non-randomized, single-arm, open-label study | Confirmed adults with fever (T ≥ 38 °C) and lung infiltration | Clinical response: resolution of fever (T < 38 °C, within 24 h); Biochemical response: time to CRP a normalization and its rate | 04331795/ University of Chicago 2020b |
Sarilumab | 30 | Spain | A randomized, open-label, single-center, comparative study | Confirmed adults with interstitial pneumoniab | Mean change in clinical status assessment using the 7-point ordinal scale at day 7, duration of hospitalization and death | 04357808/ Maria del Rosario Garcia de Vicua Pinedo 2020 |
Sarilumab | 40 | Italy | A monocentric, single-center, escalation dose open-label study | Confirmed adults (18–85) with severe interstitial pneumonia and increased levels of D-dimer (or ≥ 1000 ng/mL) | Proportion of improvement in respiratory function (time frame: 6 weeks) | 04386239/ ASST Fatebenefratelli Sacco 2020 |
Sarilumab | 1912 | US | An adaptive phase 2/3, randomized, double-blind, placebo-controlled study | Confirmed adults | Percent change in CRP (patients with serum IL-6 level greater than the upper limit of normal), proportion of patients with at least 1-point improvement using the 7-point ordinal scale (patients receiving mechanical ventilation at baseline) | 04315298/Pharmac-euticals 2020 |
Sarilumab | 60 | Italy | A one-arm, open label, multicentric phase 2 study | Confirmed hospitalized adults with specified disease or indexc | Change in a severity rating on a 7-point ordinal scale (time frame: 15 days) | 04661527/Clinica Universidad de Navarra 2020 |
Sarilumab | 120 | US | A randomized, controlled, open label study | Confirmed veterans | Intubation or death (time frame: within 14 days) | 04359901/Westyn Branch-Elliman 2020 |
Siltuximab | 200 | Spain | A randomized, open-label, phase 2 study | Confirmed hospitalized adults (≥5 days) with a maximum O2 support of 35% | Proportion of patients requiring ICU admission (time frame: 29 days) | 04329650/Judit Pich Martínez 2020 |
Siltuximab | 220 | Italy | A retrospective study | Confirmed adults needing non-invasive or invasive ventilation | Mortality (time frame: 30 days) | 04322188/Giuseppe Gritti 2020 |
Olokizumab | 372 | France | A multicenter, randomized, double-blind, adaptive placebo-controlled study | Confirmed adults with specified diseased | Proportion in response to the study therapy | 04380519/R-Pharm International 2020 |