Tocilizumab Failed to Reduce Mortality in Severe COVID-19 Patients: Results from a Randomized Controlled Clinical Trial
-
Mona Talaschian
,
Maryam Akhtari
,
Mahdi Mahmoudi
,
Shayan Mostafaei
,
Mohamadreza Jafary
,
Seyyed Mostafa Jalali
,
Kourosh Sadeghi
,
Keivan Gohari Moghadam
,
Hengameh Ansari Tadi
,
Ahmadreza Jamshidi
Abstract
The severe coronavirus disease 2019 (COVID-19) is associated with increased levels of blood interleukin (IL)-6. Therefore, it is hypothesized that modulating the levels or effects of IL-6 could diminish airway inflammation and alter the course of COVID-19.
We conducted a controlled, randomized, double-blind clinical trial on hospitalized patients with severe COVID-19 in Iran. The patients were randomly distributed by block randomization to take either standard-of-care (SOC) plus 1 or 2 doses of tocilizumab 8 mg/kg or SOC alone. The endpoint was defined by clinical improvement and discharge.
We enrolled 40 patients (20 patients in each group) from 10 July to 10 December 2020. After randomization, 1 patient in the SOC arm and 3 patients in the tocilizumab arm refused to participate and were eliminated from the study.
The mean age of participants was 59.62±15.80 in the tocilizumab group (8 women and 9 men) and 63.52±12.83 years old in the SOC group (9 women and 10 men) groups. The number of patients who recovered did not differ significantly between the tocilizumab and SOC groups (12 [70.6%][70.6%] vs. 15 [78.9%]), respectively). Hospitalization rates were also similar between the groups (Log-rank test, p=0.615; hazard ratio, 0.83; 95% CI [0.39–1.78]). The results show that tocilizumab could not be a beneficial agent for treating severe cases of COVID-19 patients and would not significantly improve clinical outcomes.
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4. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-9.
5. Castelli V, Cimini A, Ferri C. Cytokine Storm in COVID-19: "When You Come Out of the Storm, You Won't Be the Same Person Who Walked in". Front Immunol. 2020;11:2132.
6. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.
7. Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-48.
8. Saito F, Tasaka S, Inoue K-i, Miyamoto K, Nakano Y, Ogawa Y, et al. Role of Interleukin-6 in Bleomycin-Induced Lung Inflammatory Changes in Mice. Am J Respir Cell Mol Biol. 2008;38(5):566-71.
9. O'Donoghue RJJ, Knight DA, Richards CD, Prêle CM, Lau HL, Jarnicki AG, et al. Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis. EMBO Molecular Medicine. 2012;4(9):939-51.
10. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Medicine in drug discovery. 2020;5:100028.
11. Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146(1):128-36.e4.
12. Zhang J, Hao Y, Ou W, Ming F, Liang G, Qian Y, et al. Serum interleukin-6 is an indicator for severity in 901 patients with SARS-CoV-2 infection: a cohort study. J Transl Med. 2020;18(1):406.
13. Venkiteshwaran A. Tocilizumab. MAbs. 2009;1(5):432-8.
14. Rojas-Marte G, Khalid M, Mukhtar O, Hashmi AT, Waheed MA, Ehrlich S, et al. Outcomes in patients with severe COVID-19 disease treated with tocilizumab: a case-controlled study. Qjm. 2020;113(8):546-50.
15. Rossotti R, Travi G, Ughi N, Corradin M, Baiguera C, Fumagalli R, et al. Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis. J Infect. 2020;81(4):e11-e7.
16. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5.
17. Knorr JP, Colomy V, Mauriello CM, Ha S. Tocilizumab in patients with severe COVID-19: A single-center observational analysis. J Med Virol. 2020;92(11):2813-20.
18. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869.
19. Hernández-Sánchez J, Harlow L, Church C, Gaine S, Knightbridge E, Bunclark K, et al. Clinical trial protocol for TRANSFORM-UK: A therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension. Pulm Circ. 2018;8(1):2045893217735820.
20. Moots RJ, Sebba A, Rigby W, Ostor A, Porter-Brown B, Donaldson F, et al. Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials. Rheumatology (Oxford, England). 2017;56(4):541-9.
21. Hashimoto M, Fujii T, Hamaguchi M, Furu M, Ito H, Terao C, et al. Increase of hemoglobin levels by anti-IL-6 receptor antibody (tocilizumab) in rheumatoid arthritis. PLoS One. 2014;9(5):e98202.
22. Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. 2020;2(8):e474-e84.
23. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5.
24. Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19. Clinical Infectious Diseases. 2020.
25. Jordan SC, Zakowski P, Tran HP, Smith EA, Gaultier C, Marks G, et al. Compassionate Use of Tocilizumab for Treatment of SARS-CoV-2 Pneumonia. Clinical Infectious Diseases. 2020;71(12):3168-73.
26. Horby PW, Pessoa-Amorim G, Peto L, Brightling CE, Sarkar R, Thomas K, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021:2021.02.11.21249258.
27. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. New England Journal of Medicine. 2020;383(24):2333-44.
28. Veiga VC, Prats JAGG, Farias DLC, Rosa RG, Dourado LK, Zampieri FG, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84.
29. Edalatifard M, Akhtari M, Salehi M, Naderi Z, Jamshidi A, Mostafaei S, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020;56(6).
30. Dexamethasone in Hospitalized Patients with Covid-19. New England Journal of Medicine. 2020;384(8):693-704.
2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
3. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708-20.
4. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020;323(20):2052-9.
5. Castelli V, Cimini A, Ferri C. Cytokine Storm in COVID-19: "When You Come Out of the Storm, You Won't Be the Same Person Who Walked in". Front Immunol. 2020;11:2132.
6. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.
7. Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-48.
8. Saito F, Tasaka S, Inoue K-i, Miyamoto K, Nakano Y, Ogawa Y, et al. Role of Interleukin-6 in Bleomycin-Induced Lung Inflammatory Changes in Mice. Am J Respir Cell Mol Biol. 2008;38(5):566-71.
9. O'Donoghue RJJ, Knight DA, Richards CD, Prêle CM, Lau HL, Jarnicki AG, et al. Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis. EMBO Molecular Medicine. 2012;4(9):939-51.
10. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Medicine in drug discovery. 2020;5:100028.
11. Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146(1):128-36.e4.
12. Zhang J, Hao Y, Ou W, Ming F, Liang G, Qian Y, et al. Serum interleukin-6 is an indicator for severity in 901 patients with SARS-CoV-2 infection: a cohort study. J Transl Med. 2020;18(1):406.
13. Venkiteshwaran A. Tocilizumab. MAbs. 2009;1(5):432-8.
14. Rojas-Marte G, Khalid M, Mukhtar O, Hashmi AT, Waheed MA, Ehrlich S, et al. Outcomes in patients with severe COVID-19 disease treated with tocilizumab: a case-controlled study. Qjm. 2020;113(8):546-50.
15. Rossotti R, Travi G, Ughi N, Corradin M, Baiguera C, Fumagalli R, et al. Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis. J Infect. 2020;81(4):e11-e7.
16. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5.
17. Knorr JP, Colomy V, Mauriello CM, Ha S. Tocilizumab in patients with severe COVID-19: A single-center observational analysis. J Med Virol. 2020;92(11):2813-20.
18. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869.
19. Hernández-Sánchez J, Harlow L, Church C, Gaine S, Knightbridge E, Bunclark K, et al. Clinical trial protocol for TRANSFORM-UK: A therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension. Pulm Circ. 2018;8(1):2045893217735820.
20. Moots RJ, Sebba A, Rigby W, Ostor A, Porter-Brown B, Donaldson F, et al. Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials. Rheumatology (Oxford, England). 2017;56(4):541-9.
21. Hashimoto M, Fujii T, Hamaguchi M, Furu M, Ito H, Terao C, et al. Increase of hemoglobin levels by anti-IL-6 receptor antibody (tocilizumab) in rheumatoid arthritis. PLoS One. 2014;9(5):e98202.
22. Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. 2020;2(8):e474-e84.
23. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5.
24. Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19. Clinical Infectious Diseases. 2020.
25. Jordan SC, Zakowski P, Tran HP, Smith EA, Gaultier C, Marks G, et al. Compassionate Use of Tocilizumab for Treatment of SARS-CoV-2 Pneumonia. Clinical Infectious Diseases. 2020;71(12):3168-73.
26. Horby PW, Pessoa-Amorim G, Peto L, Brightling CE, Sarkar R, Thomas K, et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021:2021.02.11.21249258.
27. Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. New England Journal of Medicine. 2020;383(24):2333-44.
28. Veiga VC, Prats JAGG, Farias DLC, Rosa RG, Dourado LK, Zampieri FG, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84.
29. Edalatifard M, Akhtari M, Salehi M, Naderi Z, Jamshidi A, Mostafaei S, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020;56(6).
30. Dexamethasone in Hospitalized Patients with Covid-19. New England Journal of Medicine. 2020;384(8):693-704.
| Files | ||
| Issue | Vol 23 No 1 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i1.14956 | |
| Keywords | ||
| Coronavirus disease 2019 virus Interleukin-6 Randomized controlled trial Tocilizumab | ||
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How to Cite
1.
Talaschian M, Akhtari M, Mahmoudi M, Mostafaei S, Jafary M, Jalali SM, Sadeghi K, Gohari Moghadam K, Ansari Tadi H, Jamshidi A. Tocilizumab Failed to Reduce Mortality in Severe COVID-19 Patients: Results from a Randomized Controlled Clinical Trial. Iran J Allergy Asthma Immunol. 2024;23(1):82-96.
