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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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2018 Impact Factor: 1.847

Front. Med.    2021, Vol. 15 Issue (3) : 486-494    https://doi.org/10.1007/s11684-020-0824-3
RESEARCH ARTICLE
Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial
Dongsheng Wang1, Binqing Fu2, Zhen Peng4, Dongliang Yang5, Mingfeng Han6, Min Li7, Yun Yang3, Tianjun Yang3, Liangye Sun8, Wei Li9, Wei Shi10, Xin Yao11, Yan Ma12, Fei Xu1, Xiaojing Wang1, Jun Chen1, Daqing Xia1, Yubei Sun13, Lin Dong14, Jumei Wang14, Xiaoyu Zhu15, Min Zhang12, Yonggang Zhou2, Aijun Pan3, Xiaowen Hu1, Xiaodong Mei1(), Haiming Wei2(), Xiaoling Xu1()
1. Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
2. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
3. Intensive Care Unit, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
4. Drug Clinical Trail Institution, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
5. Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
6. Department of Respiratory Medicine, the Second People’s Hospital of Fuyang, Fuyang 236000, China
7. Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Hunan Provincial Clinical Research Center for Respiratory Diseases, Changsha 410000, China
8. Lu’an People’s Hospital Affiliated to Anhui Medical University, Lu’an 237005, China
9. Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Bengbu Medical College, Clinical Research Center for Respiratory Disease (tumor) in Anhui Province, Bengbu 233004, China
10. Department of Respiratory Medicine, Anqing Hospital Affiliated to Anhui Medical University, Anqing 246000, China
11. The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China
12. Department of Rheumatology and Immunology, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
13. Department of Oncology, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
14. Department of Endocrinology, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
15. Department of Hematology, the First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
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Abstract

Tocilizumab has been reported to attenuate the “cytokine storm” in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI −7.19%–21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 (P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI −99.17% to −17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome.

Keywords tocilizumab      coronavirus disease 2019 (COVID-19)      cytokine storm     
Corresponding Author(s): Xiaodong Mei,Haiming Wei,Xiaoling Xu   
Just Accepted Date: 30 January 2021   Online First Date: 10 March 2021    Issue Date: 18 June 2021
 Cite this article:   
Dongsheng Wang,Binqing Fu,Zhen Peng, et al. Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial[J]. Front. Med., 2021, 15(3): 486-494.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0824-3
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I3/486
Fig.1  Trial profile.
Characteristics Tocilizumab group (N = 34) Control group (N = 31) All
Age (year, median (IQR)) 63.5 (58–71) 63 (54–69) 63 (55–71)
Sex (n (%))
Male 18 (52.94) 15 (48.39) 33 (50.77)
Female 16 (47.06) 16 (51.61) 32 (49.23)
Symptom onset to randomization (median (IQR)) 20 (9–29) 24 (19–33) 23 (12–30)
Coexisting condition (n (%))
Hypertension 10 (29.41) 10 (32.26) 20 (30.77)
Diabetes 4 (11.76) 6 (19.35) 10 (15.38)
Others 8 (23.53) 9 (29.03) 17 (26.15)
Symptoms (n (%))
Cough 13 (38.24) 15 (48.39) 28 (43.08)
Shortness of breath 12 (35.29) 11 (35.48) 23 (35.38)
Fever 8 (23.53) 5 (16.13) 13 (20.00)
Phlegm 6 (17.65) 6 (19.35) 12 (18.46)
Fatigue 3 (8.82) 5 (16.13) 8 (12.31)
Vital signs (median (IQR))
Body temperature (°C) 36.6 (36.4–36.9) 36.6 (36.3–36.9) 36.6 (36.4–36.9)
Heart rate (beat/min) 80.5 (76–86) 82 (74–88) 82 (76–87)
Respiratory rate (breath/min) 20 (18–20) 20 (19–20) 20 (19–20)
Laboratory parameters (median (IQR))
White cell count (× 109/L) 6.265 (5.56–8.15) 5.77 (4.2–7.35) 6.15 (4.56–7.47)
Lymphocyte count (× 109/L) 1.085 (0.895–1.645) 1.32 (0.92–1.58) 1.185 (0.91–1.6)
C-reactive protein (mg/L) 9.95 (3.3–23.6) 6.28 (1.15–33.7) 7.58 (3–32.04)
IL-6 (pg/mL) 26.03 (12.76–58.04) 24.35 (9.895–85.325) 25.13 (10.4–77.44)
ALT (U/L) 34 (18–69) 23 (15–43) 27 (16–59)
AST (U/L) 24 (20–32) 23 (20–31) 24 (20–32)
Creatine kinase (U/L) 66 (52.1–74) 70 (60–78) 68 (55–76)
Blood urea nitrogen (mmol/L) 4.55 (3.845–5.43) 4.22 (3.5–5.1) 4.36 (3.62–5.4)
Oxygen support mode (n (%))
Nasal cannula 21 (61.76) 17 (54.84) 38 (58.46)
Mask 2 (5.88) 2 (6.45) 4 (6.15)
High flow 3 (8.82) 3 (9.68) 6 (9.23)
Air 8 (23.53) 9 (29.03) 17 (26.15)
Disease severity (n (%))
Moderate 20 (58.82) 17 (54.84) 37 (56.92)
Severe 14 (41.18) 14 (45.16) 28 (43.08)
Fingertip oxygen saturation (median (IQR)) 97 (96–98) 98 (96–99) 97 (96–98.5)
Drug combination (n (%))
Glucocorticoid 5 (14.71) 2 (6.45) 7 (10.77)
Tab.1  Baseline patient characteristics
Variables Tocilizumab group Control group Rate or median difference 95% CI
Cure rate (n (%)) 32 (94.12) (N = 34) 27 (87.10) (N = 31) −7.19, 21.23
Rate of hypoxia recovery at day 14 (n (%)) 22 (91.67) (N = 24) 12 (60.00) (N = 20) 7.52, 55.82
Length of hospitalization (median (IQR)) 26 (17–27) 24 (15–28) −4, 2
Time to negative virus (median (IQR)) 17 (12–20) 16 (12–21.5) −4, 5
Tab.2  Comparison of the primary and secondary outcomes
Variables Moderate Severe
Tocilizumab Control Rate or median difference 95% CI Tocilizumab Control Rate or median difference 95% CI
Cure rate (n (%)) 19 (95.00) (N = 20) 15 (88.24) (N = 17) −11.29, 24.81 13 (92.86) (N = 14) 12 (85.71) (N = 14) −15.62, 29.90
Rate of hypoxia recovery at day 14 (n (%)) 12 (100.00) (N = 12) 2 (33.33) (N = 6) 28.95, 100 10 (83.33) (N = 12) 10 (71.43) (N = 14) −19.79, 43.60
Rate of hypoxia worsening during hospitalization (n (%)) 1 (8.33) (N = 12) 4 (66.67) (N = 6) −99.17, −17.50 6 (50.00) (N = 12) 4 (28.57) (N = 14) −15.45, 58.31
Length of hospitalization (median (IQR)) 26 (21–27.5) 25 (19–28) −4, 5 24 (14–27) 22.5 (12–27) −7, 10
Time to negative virus (median (IQR)) 17 (13–19) 17 (14–23) −3, 7 14.5 (11.5–20.5) 11 (8–16) −13, 7
Tab.3  Subgroup analysis of primary and secondary outcomes
Fig.2  Changes in hypoxia over 14 days. (A) The difference became significant (P<0.05) on day 12 between the tocilizumab-treated group () and the controls (). (B) Recovery rate of hypoxia in moderate patients over 14 days. The difference became significant (P<0.05) on day 10 between the two groups. (C) Worsening rate of hypoxia during hospitalization in moderate patients. Less patients worsened in the tocilizumab-treated group (1/12, 8.33%) than in the controls (4/6, 66.67%) who needed an increase of inhaled oxygen concentration. (D) Recovery rate of hypoxia in severe patients over 14 days. No statistical differences were observed between patients treated with or without tocilizumab.
Variables Tocilizumab group (N = 34) Control group (N = 31)
Severe adverse event (n (%)) 0 (0.00) 1 (3.23)
Non-severe adverse event (n (%)) 20 (58.82) 4 (12.90)
Abnormal hepatic function 6 (17.65) 1 (3.23)
Leukopenia 5 (14.71) 0 (0.00)
Neutropenia 3 (8.82) 0 (0.00)
Headache 1 (2.94) 0 (0.00)
Insomnia 1 (2.94) 0 (0.00)
Rash 1 (2.94) 0 (0.00)
Constipation 1 (2.94) 0 (0.00)
Hypoglycemia 1 (2.94) 0 (0.00)
Aggravation of pulmonary disease 1 (2.94) 0 (0.00)
Diarrhea 0 (0.00) 1 (3.23)
Arrhythmia 0 (0.00) 1 (3.23)
Anemia 0 (0.00) 1 (3.23)
Tab.4  Summary of adverse events in the safety population
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