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Open access peer-reviewed chapter

A Clinical Update on Employing Tocilizumab to Fight COVID-19

Written By

Nilanjana Dhara, Sumana Saha and Saptarshi Chatterjee

Submitted: 24 June 2021 Reviewed: 03 August 2021 Published: 01 December 2021

DOI: 10.5772/intechopen.99785

Science-Based Approaches to Respond to COVID and Other Public Health Threats IntechOpen
Science-Based Approaches to Respond to COVID and Other Public Hea... Edited by Erick Guerrero

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Science-Based Approaches to Respond to COVID and Other Public Health Threats

Edited by Erick Guerrero

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Abstract

SARS-CoV-2 infection or COVID-19, currently regarded as ‘terror’ worldwide, has spread uncontrollably as a serious menace. Till date, limited effective medicines or treatments are available. The mortality and morbidity rates have increased considerably, which have been aggravated by acute respiratory distress syndrome (ARDS) and new and old cardiovascular injuries. To control COVID-19, many drugs have been taken into consideration, like ACE2 blockers, anti-inflammatory drugs, antibodies against IL-1 and anti-IL-6, Remdesivir, Dexamethasone, Hydroxychloroquine and vaccines. In this chapter, preference is given to Tocilizumab with the latest status of clinical research update available. Despite several clinical research attempts, some have yielded promising results, others are inconclusive.

Keywords

  • COVID-19
  • Tocilizumab
  • Clinical Studies
  • Antiviral drugs
  • Public Health

1. Introduction

Since December 2019, the outbreak of the novel coronavirus (SARS-CoV-2) infection (i.e. COVID-19), from Wuhan, China as a pandemic, has posed a serious threat towards mankind, treatment of which is still unknown [1]. In Jan 30, 2020, the novel coronavirus disease 2019 (COVID-19), was declared as the Sixth public health emergency epidemic by the World Health Organization [WHO] [2]. Till date there is no single drug to control it. Despite Remdesivir being used extensively for the treatment, it is still under clinical trials [3] and not beyond question [4]. The elderly, immune-compromised or people having co-morbidities led to acute respiratory distress syndrome (ARDS), cardiovascular (CV) complications, and multi-organ failure [2, 5]. Common symptoms of the disease include fever, cough, myalgia, malaise, breathlessness and diarrhea [2]. Tocilizumab (a humanized anti-IL-6 receptor antibody) is one of drugs used for the treatment of COVID-19 hospitalized patients [6]. This article summarizes all critical clinical trials to evaluate the efficacy of Tocilizumab.

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2. About the molecule

Tocilizumab is an Interleukin-6 Receptor Inhibitor, having a molecular formula of [C6428H9976N1720O2018S42]. Its molecular mass is of [145.0 kDa], CAS number: [375823-41-9]. It is a recombinant humanized monoclonal antibody used in the treatment of inflammatory and autoimmune conditions like Rheumatoid arthritis, multiple myeloma and prostate cancer, nowadays used extensively for COVID-19 treatment [7, 8, 9, 10, 11].

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3. Tocilizumab as drug

Tocilizumab, an immunosuppressive monoclonal antibody drug having the traditional name Actemra and Atlizumab, has been reported to be effective against COVID-19 in several countries such as China, France, Italy, Switzerland and Qatar Xiaoling [12, 13]. The drug is known to treat patients with hyperinflammatory syndrome and acute respiratory failure [14]. The drug is sold in the European Union (EU) under the trade name RoActemra and in the United States as Actemra [15, 16]. The drug was first approved in 2005 as an orphan drug in Japan, used in the treatment of Castleman’s disease [17]. Nowadays, Tocilizumab has acquired license for EU, to be used alone or in combination with DMARDs [disease-modifying anti-rheumatic drugs]. This combined therapy is used in the treatment of rheumatic arthritis in adults, systemic form of juvenile idiopathic arthritis (sJIA) in children above 2 years and with the polyarticular form of juvenile idiopathic arthritis (pJIA) in children more than 2 years of age [17]. This drug displays a long elimination half-life. Several studies were conducted to find out whether the drug is useful or not.

In a single centre study in Brescia [Italy], having an gathering of 100 patients, 8 mg/kg [max 800 mg] of the drug was advised to be given to patients by two consecutive intravenous infusions 12 hr. apart. Significant clinical improvement was observed in this case [18]. In another study by Alattar et al. [19] at Quatar, 25 patients having COVID-19 were administered with Tocilizumab, one to three median doses of the drug individually [4.8 mg/kg]. Tocilizumab was associated with dramatic decline in inflammatory markers, radiological improvement and reduced ventilatory support requirements [19]. In a 61-year-old man with COVID-19 symptoms, with a history of kidney transplantation, 324 mg Tocilizumab was administered via subcutaneous route along with hydroxychloroquine that helped in prevention of the disease and did not require mechanical ventilation [20]. However, contrary reports do exist, that reports that Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with COVID-19 [21].

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4. USFDA approval

The drug Actemra (tocilizumab, Genentech, Inc., South San Francisco, CA) was approved by USFDA to be used for the treatment of Rheumatoid Arthritis (RA), Giant Cell Arthritis (GCA), Polyarticular Juvenile Idiopathic Arthritis (PJIA), Systemic Juvenile Idiopathic Arthritis (SJIA) and Cytokine Release Syndrome (CRS) [22]. However, despite of recommendation of NIH on usage of Tocilizumab for COVID-19 treatment, it has not yet received approval of USFDA.

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5. Dosage of tocilizumab for COVID-19 treatment

The use of Tocilizumab is recommended as per the US NIH guidelines only for clinical trial studies [23]. The preference is mainly given to hospitalized patients with increasing oxygen demand with or without elevated markers of systemic inflammation. As per the recommendations, Tocilizumab (single intravenous [IV] dose of tocilizumab 8 mg/kg actual body weight up to 800 mg) in combination with dexamethasone (6 mg daily for up to 10 days) is advised to be administered in certain hospitalized patients experiencing rapid respiratory decompensation due to COVID-19 [24].

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6. Storage

This drug should be stored refrigerated at 2 to 8° C (36 to 46 F).

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7. Plausible mechanism of tocilizumab against COVID-19

According to a study, by the team of Haiming Wei [25], after the SARS-CoV-2 infection, CD4 + T lymphocytes are activated to become pathogenic T helper cells, generating GM-CSF (Granulo Macrophage Colony Stimulating Factor]. This leads to severe inflammatory storm created by CD14 + CD16+ inflammatory monocytes with elevated expression of IL-6. These excessive immune cells usually invade the pulmonary circulation and cause damage to the immune system, thus leading to functional disability of lungs and mortality. Therefore, drugs like Tocilizumab are administered to prevent the cytokine storm. Tocilizumab has yielded effective results as an IL-6R antagonist.

Excessive stimulation of IL-6 can cause CRS [Cytokine Release Syndrome] in hospitalized patients. The higher the level of CRS, higher is the serum peak concentration of IL-6. IL-6 binds to its receptor IL-6R and a complex is formed. IL-6R then binds to the signal transducer glycoprotein 130 (gp-130) to cause signal transduction. Two types of IL-6R are there, one is the Soluble form (sIL-6R) and the other is Membrane bound form [mIl-6R]. In classical signal transduction pathway, IL-6 binds to mIL-6R [transmembrane integral protein], and forms a complex, which then prohibits the connection of IL-6R with gp130 [integral membrane protein]. Thus no cytokine storm is produced. In the trans-signaling pathway, binding of Tocilizumab to sIl-6R, prevents the binding of IL-6R to gp130 [present on the membrane of monocytes, macrophages, dendritic cells] and thus hinders release of inflammatory storm. JAK/STAT tyrosine kinase system mediates one pathway, while Ras/mitogen-activated protein kinase (MAPK)/NF-κB-IL-6 pathway mediates the other. Tocilizumab [humanized anti-IL-6R monoclonal antibody], is thus considered a potential drug in COVID-19 treatment [26, 27].

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8. Other clinical considerations

Tocilizumab is contraindicated in immunocompromised individuals, those who use biologic immunomodulating drugs, and in patients having alanine aminotransferase >5 times the upper limit of normal; patients with gastrointestinal perforation; those having uncontrolled serious bacterial, fungal, or non-SARS-CoV-2 viral infection; absolute neutrophil count <500 cells/μL; platelet count <50,000 cells/μL. The drug should also be avoided in individuals having a known hypersensitivity to it [28]. It has been recommended to administer Dexamethasone [or an alternative corticosteroid of dosage equal to dexamethasone 6 mg] simultaneously in patients receiving Tocilizumab [9]. A patient’s clinical response to dexamethasone is initially accessed before administering Tocilizumab [29]. The combination therapy yields an adverse effect in the form of severe and disseminated strongyloidiasis infestation. Therefore, Ivermectin should be used as a prophylactic treatment [30].

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9. Side effects

The common side effects include respiratory tract infections, headache, hypertension, elevation in liver test. Rashes, erythema, oedema, itching can occur at the infection site [31]. Tuberculosis, sepsis and fungal infection are the associated infections that can occur. Hypersensitivity reactions, cancer, reactivation of herpes zoster, gastrointestinal perforation in patients with diverticulitis are also seen in some patients, though not significant [32].

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10. Clinical trial status

The process of systemic review was followed and effectiveness of the drug analyzed from the NIH, US National Library of Medicine Clinical Trial Registry (ClinicalTrials.gov). At present (till May 2021), 81 clinical studies could be traced in the name Toclilizumab [until May 2021]. 33 studies have been excluded due to non-relevance. 48 records are included in this study. Some of the studies have yielded promising initial results yet require more time for validation and declared to be effective or safe. Among the 48 trials done on Tocilizumab, 17 are in Recruiting stage, 12 trials have been concluded, 5 have been terminated, 1 has been withdrawn, 5 trials are in not yet recruiting stage and 6 are active but non recruiting. 1 among the 47 trials is in phase 1, 16 trials are in phase 2, 14 are in phase 3 trial. Analyzing the clinical trials from Table 1, it is evident that there is attempt to use Toclizumab alone or in combination with other drugs looks promising for the treatment of COVID 19 (Figure 1).

Sl. no. Clinical trial Primary objectives Study type Status Study start date Study completion date Phase Observation/ interpretation Studied by: Reference Publication
1 The Use of Tocilizumab in the Management of Patients Who Have Severe COVID-19 With Suspected Pulmonary Hyperinflammation To assess the therapeutic value of intravenous tocilizumab administered as single 8 mg/Kg dose in patients affected by SARS-CoV2 infection with a pulmonary manifestation causing hypoxia. Interventional Recruiting Apr-20 May-21 Phase 4 Not Available Hadassah Medical Center NCT04377750 Nil
2 Tocilizumab to Prevent Clinical Decompensation in Hospitalized, Non-critically Ill Patients With COVID-19 Pneumonitis To establish proof of concept that tocilizumab is effective in decreasing signs, symptoms, and laboratory evidence of COVID-19 pneumonitis in hospitalized, non-critically ill patients Interventional Completed Apr-20 Jun-20 Phase2 Not Available University of Chicago NCT04331795 Nil
3 Low-dose Tocilizumab Versus Standard of Care in Hospitalized Patients With COVID-19 [COVIDOSE-2] To establish whether low-dose tocilizumab reduces the time to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation, when compared to a tocilizumab-free standard of care and to establish whether low-dose tocilizumab is near-equivalent to high-dose tocilizumab (400 mg or 8 mg/kg) in reducing the time to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation. Interventional Recruiting Sep-20 Dec-20 Phase 2 Not Available University of Chicago NCT04479358 [33]
4 Tocilizumab in COVID-19 Pneumonia (TOCIVID-19) (TOCIVID-19) This study project includes a single-arm phase 2 study and a parallel cohort study, enrolling patients with COVID-19 pneumonia. Interventional Active not recruiting March 19, 2020 December 19, 2022 Phase 2 Not Available National Cancer Institute, Naples NCT04317092 [34, 35, 36]
5 Study to Evaluate the Efficacy and Safety of Tocilizumab Versus Corticosteroids in Hospitalized COVID-19 Patients With High Risk of Progression This study aims to compare the efficacy and safety of Methylprednisolone versus Tocilizumab in improving clinical outcomes and reducing the need for ventilator support in COVID-19 patients with moderate COVID-19 disease at risk for complications of cytokine storm. Interventional Not yet recruiting April 15, 2020 October 31, 2020 Phase 3 Not Available University of Malaya NCT04345445 Nil
6 Clinical Efficacy of Heparin and Tocilizumab in Patients With Severe COVID-19 Infection: a Randomized Clinical Trial (HEPMAB) To study the use of heparin and tocilizumab to potencially reduce inflammation and thrombogenesis in patients with severe COVID-19 infection, improving patients outcomes and survival. Interventional Recruiting November 10, 2020 December 31, 2021 Phase 3 Not Available Ludhmila Abrahão Hajjar, University of Sao Paulo NCT04600141 Nil
7 Efficacy of Tocilizumab in Modifying the Inflammatory Parameters of Patients With COVID-19 (COVITOZ-01) (COVITOZ-01) To study the unicenter, randomized, open-label clinical trial on the efficacy of tocilizumab in modifying the inflammatory parameters of patients with COVID-19. Interventional Recruiting May 4, 2020 August 4, 2020 Phase 2 Not Available Jose A Perez Molina, Hospital Universitario Ramon y Cajal NCT04435717 Nil
8 Trial of Tocilizumab for Treatment of Severe COVID-19: ARCHITECTS (ARCHITECTS) The overall objective is to evaluate the clinical efficacy and safety of tocilizumab relative to placebo among approximately 300 hospitalized adult patients who have severe COVID-19 Interventional Recruiting June 12, 2020 December 31, 2021 Phase 3 Not Available Queen’s Medical Centre NCT04412772 Nil
9 TOCILIZUMAB - An Option for Patients With COVID-19 Associated Cytokine Release Syndrome; A Single Center Experience To analyze the effectiveness of Tocilizumab in moderate to severe Covid-19 participants on the basis of predefined assessment criteria. Interventional Completed May 12, 2020 June 12, 2020 Phase 4 Not Available Aijaz Zeeshan Khan Chachar, FMH College of Medicine and Dentistry NCT04730323 Nil
10 Clinical Trial of Combined Use of Hydroxychloroquine, Azithromycin, and Tocilizumab for the Treatment of COVID-19 (TOCOVID) To evaluate the use of Tocilizumab in combination with hydroxychloroquine and azithromycin for the treatment of hospitalized adult patients with COVID-19. Interventional Recruiting April 2, 2020 Oct-20 Phase 2 Not Available Fundació Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau NCT04332094 Nil
11 Clinical Trial to Evaluate the Effectiveness and Safety of Tocilizumab for Treating Patients With COVID-19 Pneumonia To evaluate the effectiveness and safety of IV tocilizumab in patients with COVID-19 severe pneumonia who are currently hospitalized or admitted to ICU. Interventional Completed May 22, 2020 December 23, 2020 Phase 2 Not Available Fundacion SEIMC-GESIDA NCT04445272 [7]
12 Tocilizumab for Prevention of Respiratory Failure in Patients With Severe COVID-19 Infection The purpose of this study is to find out whether the study drug tocilizumab is an effective treatment for COVID-19 infection. Interventional Active, not recruiting May 1, 2020 May 1, 2022 Phase 2 Not Available Memorial Sloan Kettering Cancer Center NCT04377659 Nil
13 COVID-19: Salvage Tocilizumab as a Rescue Measure (COVIDSTORM) To Evaluate the efficacy of Tocilizumab in hospitalized patients in the inflammatory phase of COVID-19. Interventional Recruiting August 14, 2020 December 31, 2021 Phase 3 Not Available Jarmo Oksi, Turku University Hospital NCT04577534 Nil
14 Serum IL-6 and Soluble IL-6 Receptor in Severe COVID-19 Pneumonia Treated With Tocilizumab (UHID-COVID19) To assess the role of interleukin-6 (IL-6) and soluble interleukin 6 receptor (sIL-6R) as predictors of efficacy and safety outcomes in patients with severe coronavirus disease (COVID-19) pneumonia treated with tocilizumab. Observational Recruiting June 16, 2020 May 15, 2021 case only Not Available University Hospital for Infectious Diseases, Croatia NCT04359667 Nil
15 A Study in Patients With COVID-19 and Respiratory Distress Not Requiring Mechanical Ventilation, to Compare Standard-of-care With Anakinra and Tocilizumab Treatment The Immunomodulation-CoV Assessment (ImmCoVA) Study The study is designed as a randomized, controlled, single-center open-label trial to compare standard-of-care (SOC) treatment with SOC + anakinra or SOC + tocilizumab treatment in hospitalized adult subjects who are diagnosed with severe COVID 19. Interventional Recruiting June 11, 2020 Feb-21 Phase 2 Not Available Jonas Sundén-Cullberg, Karolinska University Hospital NCT04412291 Nil
16 A Trial Using ANAKINRA, TOCILIZUMAB Alone or in Association With RUXOLITINIB in Severe Stage 2b and 3 of COVID19-associated Disease (INFLAMMACOV) To use biological drugs currently available for inhibition of IL-1 (anakinra), IL-6 (tocilizumab) or IFNg signaling (ruxolitinib) in the severe forms of COVID19-associated disease. Interventional Not yet recruiting September 1, 2020 November 1, 2022 Phase 3 Not Available Assistance Publique Hopitaux De Marseille NCT04424056 Nil
17 Tocilizumab Versus Methylprednisolone in the Cytokine Release Syndrome of Patients With COVID-19 This study compare the efficacy and safety of tocilizumab versus methylprednisolone in the cytokine release syndrome of patients with COVID-19 Interventional Not yet recruiting May-20 Aug-20 Phase 2 Not Available José Raimundo Araujo de Azevedo, Hospital Sao Domingos NCT04377503 [8, 37, 38, 39, 40, 41, 42, 43]
18 Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19) (CORON-ACT) To evaluate whether treatment with TCZ reduces the severity and mortality in patients with COVID-19. Interventional Terminated April 26, 2020 September 27, 2020 Phase 2 Not Available University Hospital Inselspital, Berne NCT04335071 [2, 9, 10, 28, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53]
19 A Study to Investigate Intravenous Tocilizumab in Participants With Moderate to Severe COVID-19 Pneumonia (MARIPOSA) To Investigate Intravenous Tocilizumab in Participants With Moderate to Severe COVID-19 Pneumonia Interventional Completed May 5, 2020 August 12, 2020 Phase 2 Not Available Hoffmann-La Roche NCT04363736 Nil
20 Efficacy and Safety of Tocilizumab in the Treatment of SARS-Cov-2 Related Pneumonia (TOSCA) This is a prospective observational clinical study and it is aimed at verifying tocilizumab efficacy and safety in patients with COVID-19 complicated by acute distress respiratory syndrome (ARDS) and CRS. Observational Recruiting April 1, 2020 March 31, 2021 Observational Model: Cohort Not Available Prof. Roberto Giacomelli, University of L’Aquila NCT04332913 [2, 9, 12, 28, 54, 55, 56, 57, 58, 59, 60, 61, 62]
21 Efficacy of Tocilizumab on Patients With COVID-19 To test the effect of Tocilizumab on multi-organ dysfunction in a phase 3 randomized controlled trial among hospitalized patients with COVID-19 infection. Interventional Completed April 20, 2020 August 27, 2020 Phase 3 Tocilizumab provided no benefit in prevention of death (the primary outcome) or reducing the risk of clinical worsening (secondary outcomes). Stone, John H, M.D., M.P.H, Massachusetts General Hospital NCT04356937 [21]
22 A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia (COVACTA) This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of tocilizumab (TCZ) compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with severe COVID-19 pneumonia. Interventional Completed April 3, 2020 July 28, 2020 Phase 3 No difference was noticed between tocilizumab and placebo for clinical status (including death) at Day 28 (the primary outcome), but tocilizumab exhibited a shorter time to recovery and shorter length of ICU stay (secondary outcomes). Hoffmann-La Roche NCT04320615 Nil
23 Efficacy and Safety of Remdesivir and Tociluzumab for the Management of Severe COVID-19: A Randomized Controlled Trial To evaluate the efficacy of Remdesivir and Tocilizumab as a treatment for severe Acute Respiratory Distress Syndrome (ARDS) caused by Coronavirus disease 2019 (COVID-19). Interventional Completed August 15, 2020 February 10, 2021 Phase 3 Not Available Abu Taiub Mohammed Mohiuddin Chowdhury, First Affiliated Hospital Xi’an Jiaotong University NCT04678739 Nil
24 A Study to Evaluate the Efficacy and Safety of Tocilizumab in Hospitalized Participants With COVID-19 Pneumonia (EMPACTA) This study (EMPACTA) will a) evaluate the efficacy and safety of tocilizumab (TCZ) compared with a placebo in combination with standard of care (SOC) in hospitalized participants with COVID-19 pneumonia, and b) include an optional substudy to explore the long-term sequelae of resolved COVID-19 pneumonia. Interventional Recruiting May 14, 2020 December 1, 2021 Phase 3 Tocilizumab lowered rates of mechanical ventilation or death by Day 28 but provided no benefit in 28-day mortality. Genentech, Inc. NCT04372186 [63]
25 A Study to Evaluate the Efficacy and Safety of Remdesivir Plus Tocilizumab Compared With Remdesivir Plus Placebo in Hospitalized Participants With Severe COVID-19 Pneumonia (REMDACTA) This study will evaluate the efficacy and safety of combination therapy with remdesivir plus tocilizumab compared with remdesivir plus placebo in hospitalized patients with COVID-19 pneumonia. Interventional Completed June 16, 2020 March 8, 2021 Phase 3 Not Available Hoffmann-La Roche NCT04409262 Nil
26 Safety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 With Inflammatory Markers (TOCIBRAS) To evaluate the efficacy and safety of Tocilizumab, which rapidly reduces the inflammation process through inhibition of IL-6 in patients with moderate to severe COVID-19 with increased inflammatory markers. Interventional Terminated May 8, 2020 July 21, 2020 Phase 3 Tocilizumab showed no benefit in this study Dr Rozana Mesquita Ciconelli, Beneficência Portuguesa de São Paulo NCT04403685 [64]
27 Anti-il6 Treatment of Serious COVID-19 Disease With Threatening Respiratory Failure (TOCIVID) To compare the effect of either one of three IL-6 inhibitor administrations, relative to the standard of care, on time to independence from supplementary oxygen therapy, measured in days from baseline to day 28, in patients with severe SARS-CoV-2 pneumonia. Interventional Terminated April 5, 2020 October 8, 2020 Phase 2 Not Available Marius Henriksen, Frederiksberg University Hospital NCT04322773 Nil
28 Treatment of COVID-19 Patients With Anti-interleukin Drugs (COV-AID) To test the safety and effectiveness of individually or simultaneously blocking IL-6 and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome Interventional Active, not recruiting April 3, 2020 Mar-21 Phase 3 Not Available Bart N. Lambrecht, University Hospital, Ghent NCT04330638 [65]
29 CORIMUNO-19 - Tocilizumab Trial - TOCI (CORIMUNO-TOCI) (CORIMUNO-TOC) To determine the therapeutic effect and tolerance of Tocizilumab in patients with moderate, severe pneumonia or critical pneumonia associated with Coronavirus disease 2019 (COVID-19) Interventional Active, not recruiting March 30, 2020 December 31, 2021 Phase 2 In COVID-19 Patients Tocilizumab led to improved ventilator-free survival at Day 14 suggesting possible benefit, but the clinical implications are unclear as there was no difference in survival for tocilizumab vs. usual care through Day 28. Assistance Publique - Hôpitaux de Paris NCT04331808 [66]
30 Investigational Treatments for COVID-19 in Tertiary Care Hospital of Pakistan To study the role of Investigational Therapies Alone or in Combination to Treat Moderate, Severe and Critical COVID-19 Interventional Completed April 1, 2020 July 20, 2020 Not applicable Not Available sultan mehmood kamran, UNICEF NCT04492501 [67, 68, 69, 70, 71, 72, 73]
31 Tocilizumab in Coronavirus-19 Positive Patients To determine the impact of adjunctive Tocilizumab (TCZ) to standard of care on the reduction of hyperinflammation-related mortality in COVID-19. Interventional Not yet recruiting July 30, 2020 Jun-21 Phase 3 Not Available University of Calgary NCT04423042 [8, 71, 74]
32 Tocilizumab for the Treatment of Cytokine Release Syndrome in Patients With COVID-19 (SARS-CoV-2 Infection) TO compare the effect of adding tocilizumab to standard of care versus standard of care alone in treating cytokine release syndrome (CRS) in patients with SARS-CoV-2 infection. CRS is a potentially serious disorder caused by the release of an excessive amount of substance that is made by cells of the immune system (cytokines) as a response to viral infection Interventional Withdrawn April 7, 2020 June 2, 2020 Phase 3 Not Available Ajay Nooka, Emory University NCT04361552 Nil
33 Comparison of Tocilizumab Plus Dexamethasone vs. Dexamethasone for Patients With Covid-19 (TOCIDEX) To determine the therapeutic effect and tolerance of Tocilizumab combined with Dexamethasone in patients with moderate, severe pneumonia or critical pneumonia associated with Coronavirus disease 2019 (COVID-19). Interventional Recruiting July 16, 2020 December 31, 2021 Phase 2 Not Available Assistance Publique - Hôpitaux de Paris NCT04476979 Nil
34 Toclizumam Versus Dexamethasone in Severe Covid-19 Cases To study randomized controlled trial comparing survival benefit of Tocilizumab therapy with dexamethasone in patients with severe COVID 19 Interventional Completed March 1, 2020 August 5, 2020 Not applicable Not Available Alaa Rashad, South Valley University NCT04519385 Nil
35 Tocilizumab for SARS-CoV2 (COVID-19) Severe Pneumonitis To test the hypothesis that an anti-IL6 treatment can be effective in calming the virus-induced cytokine storm, blocking deterioration of lung function or even promoting a rapid improvement of clinical conditions, preventing naso-tracheal intubation and/or death. Interventional Active, not recruiting March 12, 2020 May-20 Phase 2 Not Available Armando Gabrielli, Università Politecnica delle Marche NCT04315480 [75, 76, 77, 78, 79]
36 Personalized Immunotherapy for SARS-CoV-2 (COVID-19) Associated With Organ Dysfunction (ESCAPE) To conduct one trial of personalized immunotherapy in patients with SARS-CoV-2 (COVID-19) associated with organ dysfunction and with laboratory findings of macrophage activation syndrome or immune dysregulation. Interventional Completed April 2, 2020 January 8, 2021 Phase 2 Not Available Hellenic Institute for the Study of Sepsis NCT04339712 Nil
37 Theranostic Implication of Complementary Medicines Against Interleukin Receptors and Gp-130 Proteins To estimate the relationship of severity of disease with gp-130 and IL-6 Interventional Completed July 23, 2020 December 10, 2020 Not Applicable Not Available Dr Muhammad Mansoor Hafeez, University of Lahore NCT04690920 Nil
38 Tocilizumab vs. CRRT in Management of Cytokine Release Syndrome (CRS) in COVID-19 (TACOS) To study Tocilizumab associated with better clinical outcomes, such as decreased systemic inflammation, improved survival rate, better hemodynamic and improved of respiratory distress. Observational Recruiting February 20, 2020 June 20, 2020 Cohort Not Available YIKAI YU, Tongji Hospital NCT04306705 Nil
39 Tocilizumab for Patients With Cancer and COVID-19 Disease To enhance access to tocilizumab for patients who cannot participate in the randomized COVACTA trial with specific emphasis on patients with cancer, especially those who belong to high-risk and minority populations and children. Interventional Terminated May 28, 2020 January 14, 2021 Phase 2 Not Available National Cancer Institute (NCI) NCT04370834 Nil
40 Favipiravir Combined With Tocilizumab in the Treatment of Corona Virus Disease 2019 To evaluate the efficacy and safety of favipiravir combined with tocilizumab in the treatment of corona virus disease 2019 Interventional Recruiting March 8, 2020 May-20 Not Applicable Not Available Guiqiang Wang, Peking University First Hospital NCT04310228 Nil
41 Tocilizumab in COVID-19 Lahore General Hospital (TC19LGH) This is intervention single-center study, done at Lahore General Hospital in which 95 beds are allocated for COVID-19 patients including ICUs and HDUs. Interventional Recruiting May 1, 2020 December 30, 2020 Phase 1 Not Available Dr. M.Irfan Malik, Lahore General Hospital NCT04560205 [80, 81, 82, 83]
42 Comparison of Tocilizumab Versus Tocilizumab/Infliximab in Patients With COVID-19-associated Cytokine Storm Syndrome To compare the outcomes of a large cohort of patients with moderate and severe COVID-19 pneumonia treated with tocilizumab in addition to standard management, with those of concomitantly hospitalized patients who received infliximab and tocilizumab in addition to standard management. Observational Recruiting December 1, 2020 June 1, 2021 Cohort Not Available Neven Sarhan, Misr International University NCT04734678 Nil
43 Assessment of Efficacy and Safety of Tocilizumab Compared to DefeROxamine, Associated With Standards Treatments in COVID-19 (+) Patients Hospitalized In Intensive Care in Tunisia (TRONCHER) To study the assessment of Efficacy and Safety of Tocilizumab Compared to DefeROxamine, associated with standards treatments in COVID-19 (+) patients, Hospitalized In Intensive care in Tunisia. Interventional Not yet recruiting September 4, 2020 October 4, 2020 Phase 3 Not Available Dr Jalila Ben Khelil, Abderrahmane Mami Hospital NCT04361032 Nil
44 Tocilizumab Treatment in Patients With COVID-19 To study the impact of the administration of Tocilizumab on the evolution of the acute respiratory distress syndrome (ARDS) in patients with severe or critical SARS-CoV-2 infection Interventional Active, not recruiting June 1, 2020 August 1, 2021 Phase 2 Not Available Oscar Gerardo Arrieta Rodríguez, Instituto Nacional de Cancerologia de Mexico NCT04363853 [1, 2, 5, 54, 77, 84, 85, 86, 87, 88, 89, 90, 91]
45 Pharmacokinetics, Pharmacodynamics, and Safety Profile of Understudied Drugs Administered to Children Per Standard of Care (POPS) (POPS or POP02) To evaluate the PK of understudied drugs currently being administered to children per SOC as prescribed by their treating provider. Observational Recruiting March 5, 2020 April 24, 2024 Prospective Not Available Duke University NCT04278404 [92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142]
46 Efficacy of Early Administration of Tocilizumab in COVID-19 Patients To study early administration of Tocilizumab compared to late administration of Tocilizumab can reduce the number of patients with COVID-19 pneumonia who require mechanical ventilation. Interventional Terminated March 31, 2020 June 6, 2020 Phase 2 Not Available Azienda Unità Sanitaria Locale Reggio Emilia NCT04346355 [143]
47 Comparative Therapeutic Efficacy and Safety of Different Antiviral and Anti Inflammatory Drugs in COVID-19 Patients. To study the comparison of the outcomes of a large cohort of moderate and severe COVID-19 patients received different Antiviral and Anti Inflammatory Drugs. Interventional Recruiting October 1, 2020 April 5, 2021 Phase 4 Not Available Ahmed Essam, October 6 University NCT04779047 Nil
48 Anti-IL6 and Corticosteroid Monotherapy vs. Combination in COVID-19 To evaluate the safety and efficacy of anti-IL6 alone vs. anti-IL6 corticosteroid combination in patients with COVID-19 pneumonia Observational Recruiting July 22, 2020 July 22, 2021 Other Not Available King Faisal Specialist Hospital & Research Center NCT04486521 [144]

Table 1.

Update of the status of clinical trials for the use of tocilizumab in the treatment of COVID-19.

Figure 1.

Status of clinical trials and stage: tocilizumab.

11. Comparing tocilizumab with other drugs involved in COVID-19 treatment

Several drugs employed for the treatment of COVID-19 through clinical trials are: Remdesivir, Tocilizumab, Baricitinib, Sarilumab and Hydroxychloroquine. In terms of clinical research output Remdesivir emerges as frontrunner, while Tocilizumab may be considered as a potential drug candidate against COVID-19. Despite the initial attempt of drug repurposing by using Hydroxychloroquine to treat COVID-19, there were limited encouraging results for which, its administration was removed from the line of treatment in various countries. A comparison between Tocilizumab and other drugs involved in the treatment of COVID-19 is presented in Table 2.

Sl. no. Name of the drug Mechanism of action Clinical trial status Significant findings References
1 Tocilizumab Tocilizumab has rendered effective results as an IL-6R antagonist, to prevent the cytokine storm. At present, 87 clinical studies could be traced in the name Tocilizumab. Out of which, 1 is in early phase 1; 3 are in phase1; 33 are in phase 2; 24 are in phase 3; and 4 are in phase 4. Although Tocilizumab is approved by the USFDA (Not for COVID-19 treatment), still its positive effects cannot be predicted in all patients. Among some hospitalized patients with severe or critical COVID-19,a shorter time to recovery and shorter length of ICU stay was seen in those who received this drug. It still it cannot be referred to as an anti-viral drug and may only be effective in patients having inflammation and lung damage caused by the coronavirus. —
2 Remdesivir The drug inhibits the synthesis of viral RNA by delayed chain termination method. At present, 110 clinical studies could be traced in the name Remdesivir. Of which 1 study is in early phase 1; 9 are in phase 1; 35 are in phase 2; 41 are in phase 3; 3 are in phase 4. The USFDA approved drug Remdesivir has been used alone or in combination with other drugs to curb the severity of COVID-19. However it still needs to be administered to a large mass to predict the significant outcomes. [3, 4]
3 Baricitinib Baricitinib is an inhibitor of JAK-1 and JAK-2, which dampens the proinflammatory cytokine signaling. It also inhibits AP2-associated protein kinase [AAK-1]. At present, 20 studies could be traced in the name of Baricitinib. Out of which, 10 are in phase2; 11 are in phase 3; and 1 is in phase 4 The USFDA approved drug appears to be relatively safe and well tolerated when used for rheumatoid arthritis. Nowadays they are used for COVID-19 treatment, combined with Remdesivir. Mortality rates have been significantly lowered. [145, 146]
4 Sarilumab Sarilumab is a human recombinant IgG1 antibody that binds to both forms of IL-6R, inhibiting the IL-6 mediated signaling. At present, 17 clinical studies could be traced in the name Sarilumab, out of which 1 is in phase1; 6 are in phase 2; 1 is in phase 2,3; 3 are in phase 1 and 1 is in phase 4. The drug has been already approved by USFDA for treatment of patients with COVID-19.No benefit of Sarilumab with respect to time to clinical improvement or mortality was observed in case of this drug. [147]
5 Hydroxychloroquine The drug increases endosomal pH, interferes with the glycosylation of cellular receptors of SARS-COV and blocks viral infection. At present, 281 clinical studies could be traced in the name Hydroxychloroquine. Out of which 5 studies are in early phase 1; 14 are in phase 1; 88 are in phase 2; 116 are in phase 3; 24 are in phase 4. The drug has not been approved by FDA for treatment of COVID-19 patients. No significant observation can be noted, as trials are still ongoing.

Table 2.

Comparing tocilizumab with other drugs employed for COVID-19 treatment.

12. Summarizing prominent publications on tocilizumab related to COVID treatment

Apart from several clinical research outcomes (summarized in Table 1) there has been several publications revealing scientific information on the mechanism, application and prospect of the drug candidate Tocilizumab for COVID-19 treatment. There are more than 30 publications found in PubMed (https://pubmed.ncbi.nlm.nih.gov/) in the year 2021 among which few significant ones are summarized in following Table 3.

Sl. no. Year of publication Title of publication Significant observation Reference
1 2020 Tocilizumab in patients hospitalized with Covid-19 Pneumonia This trial consisted of more than 25% of the patients who were older than 65 years of age, more than 75% having at least one coexisting disease condition, and greater than 80% were in a minority racial or ethnic group. Scientists found that the possibility of progression to mechanical ventilation or death by day 28 was considerably lower among patients who received tocilizumab plus standard care in comparison to those who received placebo plus standard care. [148]
2 2020 Tocilizumab in patients with severe COVID-19: a retrospective cohort study This trial consisted of 1351 patients who were admitted to the recruiting centres. 544 (40%) patients with severe pneumonia were also taken into consideration. There were 359 (66%) male patients, with a median age of 67 years. Tocilizumab [administered intravenously or subcutaneously] plus standard care could reduce the mortality rate or curb the usage of mechanical ventilation in severe COVID-19 patients compared to those who received only standard care as per shown in this study. [149]
3 2020 Impact of tocilizumab administration on mortality in severe COVID-19. In this trial 84 patients were administered with tocilizumab and 190 patients were not treated with tocilizumab. Scientists could not predict or conclude any favorable outcome from this trial. [150]
4 2020 Why Tocilizumab could an effective treatment for severe COVID-19? The IL-6 antagonist, Tocilizumab is highly recommended by scientists to curb the mortality of severe COVID-19. Scientists hope this drug could be beneficial in curbing the severity of COVID-19 pandemic. This study analyses the beneficial effects of this drug. [151]
5 2020 Effective treatment of severe COVID-19 patients with Tocilizumab. The average age of the subjects in this study were 56.8 ± 16.5 y and ranged from 25 to 88 years. Out of them in 21 patients, improvement of the rate of deterioration of COVID-19 patients was observed by scientists, which suggested that this drug could be effective enough to treat patients with COVID-19. [152]
6 2020 Hydroxychloroquine and tocilizumab therapy in COVID-19 patients- An observational study. In this retrospective observational cohort study consisting of 2512 patients hospitalized COVID-19 patients, within a 13- hospital network, scientists could not predict any favorable outcome. On the contrary, the use of Tocilizumab alone yielded effective results, that is, it helped in reducing the death rate. [153]
7 2020 Time to Reassess Tocilizumab’s Role in COVID-19 Pneumonia. The efficacy of the drug was unclear from this study compared to other observational studies. [154]
8 2021 Tocilizumab in COVID-19: some clarity amid controversy. The recovery trial showed some evidence regarding the use of Tocilizumab in COVID-19 patients. Scientists found that only 31% of the population receiving Tocilizumab showed promises of recovery as compared to those receiving placebo. Still, this drug therapy needs to be combined with other drugs for better outcomes. [155]
9 2021 Effectiveness of Tocilizumab in patients hospitalized with COVID-19. Scientists found that Tocilizumab may be effective in diminishing the health hazards of patients with moderate to severe COVID-19 – associated pneumonia and elevated CRP level. Yet it needs to be administered to a large mass to fathom its efficacy. [156]
10 2021 Tocilizumab in hospitalized patients with severe Covid-19 Pneumonia. Scientists could not gather any significant clinical status or predict any lowering of mortality rate in comparison to placebo at 28 days. [157]

Table 3.

Prominent publications reporting the treatment of COVID-19 using Tocilizumab.

13. Conclusion

Although the drug Tocilizumab has shown to reduce mortality and morbidity, still it cannot be referred to as an anti-COVID drug and may only be effective in patients having inflammation and lung damage caused by the coronavirus. Moreover the sensitivity of the drug limits its usage to a specific age and certain patients. Moreover, Tocilizumab is not-yet approved by the USFDA. This drug brings a ray of hope, as it’s very much effective in mitigating immune damage, lung functional injuries and arterial oxygen saturation. Scientists therefore hope that this drug could be beneficial to a large mass of population in diminishing the adverse effects of the pandemic.

Conflict of interest

The authors declare that they neither have any conflict of interest nor is involved directly or indirectly with any clinical trials of any of the drugs mentioned in the chapter.

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Written By

Nilanjana Dhara, Sumana Saha and Saptarshi Chatterjee

Submitted: 24 June 2021 Reviewed: 03 August 2021 Published: 01 December 2021

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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