Safety and Effectiveness Study of Tocilizumab in Patients With Severe COVID-19

Safety and Effectiveness Observational Study of Anti IL-6 Tocilizumab in Hospital Admitted Patients With Severe COVID-19 Pneumonia.

Retrospective observational cohort study to evaluate the safety and effectiveness of tocilizumab in the treatment of severe COVID-19 pneumonia

Study Overview

• Status: Recruiting
• Conditions: Tocilizumab; Severe COVID 19 Pneumonia
• Intervention / Treatment: Drug: Tocilizumab

Detailed Description

Since the appearence of the disease today known as COVID-19 there has been multiple interventions to try to gain knowledge on the subject and obtain a benefitial effect treating this condition.

Tocilizumab, a monoclonal antibody targeting IL-6 receptor has arised as an alternative for the treament of COVID-19 pneumonia.

It is a drug used for the treatment of rhemautoid arthritis and other autoimmune diseases as well as approved in recent years for the treatment of the cytokine release syndrome (CRS) in CAR-T therapy.

It is based in this last premise that the benefitial effect on COVID-19 pneumonia has been sought of. According to investigation into the physiopathology of the virus, it is supposed to trigger the inflamattory cascade that generates damage to lungs and creates the most severe cases of the disease. These findings could imply that tocilizumab may serve to interrupt this cytokine storm and prevent the progression of the disease.

The aim of the study is to evaluate the effectiveness and safety of tocilizumab in the treatment of severe cases of COVID-19. For that purpose, an observational retrospective cohort study has been designed comparing two populations that share the same indication for the treatment with tocilizumab. One having received the drug and the other in a close previous period of time that has not received it because of lack of availability or generalisation of its use. Mortality will be assesed as well as other variables such as need for mechanical ventilation and adverse effects of tocilizumab.

• Study Type: Observational
• Enrollment (Anticipated): 300

Contacts and Locations

• Study Contact: Name: Anaclara Murujosa, MD; Phone Number: +5491157033547; Email: anaclara.murujosa@hospitalitaliano.org.ar
• Study Contact Backup: Name: Diego H Giunta, MD, MPH, PhD; Phone Number: 4806 +54 11 4959 0200; Email: diego.giunta@hospitalitaliano.org.ar

Study Locations

• Argentina
  • Caba
    • Ciudad autónoma de Buenos Aires, Caba, Argentina, 1199
      • Recruiting
      • Hospital Italiano de Buenos Aires
      • Contact: Anaclara Murujosa, MD; Phone Number: +5491157033547; Email: anaclara.murujosa@hospitalitaliano.org.ar
      • Contact: Diego Hernán Giunta, MD, MPH, University SoTL, PhD; Phone Number: 4806 +54 11 4959 0200; Email: diego.giunta@hospitalitaliano.org.ar

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients admitted to hospital with severe COVID-19 pneumonia that have progressed in the requirement of oxygen or need of non-rebreathing mask that have an active inflammatory state defined as persistent fever, CRP over 50 mg/dL or D dimer over 1000 ng/dL.

Description

Inclusion Criteria:

• Hospital admitted patients with severe COVID-19 pneumonia (Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50%).
• Confirmed diagnosis of Covid-19 through qualitative polymerase-reverse transcriptase (qRT-PCR -GeneDX Co, Ltd o similar) or antigen rapid test.

• Patients who received tocilizumab or shared the same indication but did not received it (same period of time or previous close period) that:

  • Progress in the requirement of supplemental oxygen (over 3L/m) and/or use of non-rebreathing mask with 8L/m or more to mantain a Sp02>= 94%.

AND

* Active inflammatory state defined as persistent fever > 38°C (defined as 2 or more measurements in a 24-hour period from hospital admission) despite the use of dexamethasone in the previous 48 hours OR C reactive Protein > 50 mg /dL OR D Dimer > 1000 ng/mL.

Exclusion Criteria:

• Asymptomatic, mild or moderate COVID-19 disease.
• Patients with some type of immunosupression (HIV, use of immunomodulatory drugs, organ-trasplant receipt patients)
• Pregnant or breast-feeding
• Patients with augmented risk of bowel perforation (history of diverticulitis or bowel surgery in the three months prior to the study entrance date)
• Known severe allergic reactions to TCZ
• Suspected active bacterial, fungal, viral, or other infection (besides COVID-19)
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN) at screening
• Absolute neutrophil count (ANC) < 1000/mL at screening
• Platelet count < 50,000/mL at screening
• Positive Hepatitis B Surface (HbS) antigen
• Procalcitonine > 0,5 ng/mL
• Day of symptom onset before day 7 or after day 12
• Patients with dementia
• Patients non eligible to progress to mechanical ventilation because of frailty/comorbidites according to medical decision.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tocilizumab; Group that received tocilizumab (8mg/kg, maximum dose 800 mg, only once) while being admitted with severe COVID-19 pneumonia.	Drug: Tocilizumab; Tocilizumab received as a single intravenous infusion over the period of 60 minutes. Dose of 8 mg/kg, maximum dose of 800 mg.
Non-tocilizumab; Group that did not receive tocilizumab but share the same indication according to the elegibility criteria for it as the tocilizumab group while admitted with severe COVID-19 pneumonia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
28-day mortality	28-day mortality	28 days from hospital admission
Percentage of patients in invasive mechanical ventilation at day 28	Percentage of patients that received invasive mechanical ventilation at day 28 following hospital admission.	28 days from hospital admission
Clinical status during follow-up at 28th day	Ordinal outcome with seven mutually exclusive categories to describe the patient's clinical status during follow-up. The six categories are: (1) Discharged or ready for discharge; (2) Admitted to non-ICU ward without oxygen; (3) admitted to non-ICU ward but requiring supplemental oxygen; (4) admitted to ICU or non ICU ward requiring high flow nasal canula or other non invasive mechanical ventilation; (5) admitted to ICU ward requiring invasive mechanical ventilation (6) admitted to ICU ward requiring extracorporeal membrane oxygenation or invasive mechanical ventilation plus other vital organ support; (7) death	28th day from hospital admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality rate		Days 14 and 21
Percentage of patients in invasive mechanical ventilation at day 14 and 21		Days 14 and 21
Percentage of patients with hospital discharge at day 7, 14, 21 and 28		Days 7, 14, 21 and 28
Time to hospital discharge	Time from hospital admission to hospital discharge	Up to 60 days
Percentage of patients admitted to ICU-ward at day 28	Percentage of patients admitted to ICU-ward at day 28 from hospital admission	28th day from hospital admission
Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status		Up to 60 days
Percentage of patients with need of tracheostomy at day 28 of hospital admission		28th day from hospital admission
Time to mechanical ventilation from hospital admission		Up to 28 days
Days of ICU admission		Up to 60 days
Time to ICU discharge from hospital admission	Time to ICU discharge from hospital admission in the patients subgroup that required ICU admission.	Up to 60 days
Percentage of patients with adverse effects / serious adverse effects		Up to 28 days
Percentage of superimposed infections		28th day from hospital admission

Collaborators and Investigators

• Sponsor: Hospital Italiano de Buenos Aires

Publications and helpful links

General Publications

• Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, Bruzzi P, Boni F, Braglia L, Turra C, Ballerini PF, Sciascia R, Zammarchi L, Para O, Scotton PG, Inojosa WO, Ravagnani V, Salerno ND, Sainaghi PP, Brignone A, Codeluppi M, Teopompi E, Milesi M, Bertomoro P, Claudio N, Salio M, Falcone M, Cenderello G, Donghi L, Del Bono V, Colombelli PL, Angheben A, Passaro A, Secondo G, Pascale R, Piazza I, Facciolongo N, Costantini M; RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):24-31. doi: 10.1001/jamainternmed.2020.6615.
• RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17.
• Rubbert-Roth A, Furst DE, Nebesky JM, Jin A, Berber E. A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases. Rheumatol Ther. 2018 Jun;5(1):21-42. doi: 10.1007/s40744-018-0102-x. Epub 2018 Mar 3.
• Zhu J, Pang J, Ji P, Zhong Z, Li H, Li B, Zhang J. Elevated interleukin-6 is associated with severity of COVID-19: A meta-analysis. J Med Virol. 2021 Jan;93(1):35-37. doi: 10.1002/jmv.26085. Epub 2020 Oct 30. No abstract available.
• Stone JH, Frigault MJ, Serling-Boyd NJ, Fernandes AD, Harvey L, Foulkes AS, Horick NK, Healy BC, Shah R, Bensaci AM, Woolley AE, Nikiforow S, Lin N, Sagar M, Schrager H, Huckins DS, Axelrod M, Pincus MD, Fleisher J, Sacks CA, Dougan M, North CM, Halvorsen YD, Thurber TK, Dagher Z, Scherer A, Wallwork RS, Kim AY, Schoenfeld S, Sen P, Neilan TG, Perugino CA, Unizony SH, Collier DS, Matza MA, Yinh JM, Bowman KA, Meyerowitz E, Zafar A, Drobni ZD, Bolster MB, Kohler M, D'Silva KM, Dau J, Lockwood MM, Cubbison C, Weber BN, Mansour MK; BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Dec 10;383(24):2333-2344. doi: 10.1056/NEJMoa2028836. Epub 2020 Oct 21.
• RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0.
• REMAP-CAP Investigators; Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, Arabi YM, Annane D, Beane A, van Bentum-Puijk W, Berry LR, Bhimani Z, Bonten MJM, Bradbury CA, Brunkhorst FM, Buzgau A, Cheng AC, Detry MA, Duffy EJ, Estcourt LJ, Fitzgerald M, Goossens H, Haniffa R, Higgins AM, Hills TE, Horvat CM, Lamontagne F, Lawler PR, Leavis HL, Linstrum KM, Litton E, Lorenzi E, Marshall JC, Mayr FB, McAuley DF, McGlothlin A, McGuinness SP, McVerry BJ, Montgomery SK, Morpeth SC, Murthy S, Orr K, Parke RL, Parker JC, Patanwala AE, Pettila V, Rademaker E, Santos MS, Saunders CT, Seymour CW, Shankar-Hari M, Sligl WI, Turgeon AF, Turner AM, van de Veerdonk FL, Zarychanski R, Green C, Lewis RJ, Angus DC, McArthur CJ, Berry S, Webb SA, Derde LPG. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Apr 22;384(16):1491-1502. doi: 10.1056/NEJMoa2100433. Epub 2021 Feb 25.
• Angriman F, Ferreyro BL, Burry L, Fan E, Ferguson ND, Husain S, Keshavjee SH, Lupia E, Munshi L, Renzi S, Ubaldo OGV, Rochwerg B, Del Sorbo L. Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context. Lancet Respir Med. 2021 Jun;9(6):655-664. doi: 10.1016/S2213-2600(21)00139-9. Epub 2021 Apr 27.
• McCreary EK, Angus DC. Efficacy of Remdesivir in COVID-19. JAMA. 2020 Sep 15;324(11):1041-1042. doi: 10.1001/jama.2020.16337. No abstract available.
• Zhang X, Peck R. Clinical pharmacology of tocilizumab for the treatment of patients with rheumatoid arthritis. Expert Rev Clin Pharmacol. 2011 Sep;4(5):539-58. doi: 10.1586/ecp.11.33.
• Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Crit Care. 2020 Jun 16;24(1):353. doi: 10.1186/s13054-020-03062-7.
• Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, Ravaud P; CORIMUNO-19 Collaborative Group. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021 Jan 1;181(1):32-40. doi: 10.1001/jamainternmed.2020.6820. Erratum In: JAMA Intern Med. 2021 Jan 1;181(1):144. JAMA Intern Med. 2021 Jul 1;181(7):1021.
• Veiga VC, Prats JAGG, Farias DLC, Rosa RG, Dourado LK, Zampieri FG, Machado FR, Lopes RD, Berwanger O, Azevedo LCP, Avezum A, Lisboa TC, Rojas SSO, Coelho JC, Leite RT, Carvalho JC, Andrade LEC, Sandes AF, Pintao MCT, Castro CG Jr, Santos SV, de Almeida TML, Costa AN, Gebara OCE, de Freitas FGR, Pacheco ES, Machado DJB, Martin J, Conceicao FG, Siqueira SRR, Damiani LP, Ishihara LM, Schneider D, de Souza D, Cavalcanti AB, Scheinberg P; Coalition covid-19 Brazil VI Investigators. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021 Jan 20;372:n84. doi: 10.1136/bmj.n84.
• Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, Criner GJ, Kaplan-Lewis E, Baden R, Pandit L, Cameron ML, Garcia-Diaz J, Chavez V, Mekebeb-Reuter M, Lima de Menezes F, Shah R, Gonzalez-Lara MF, Assman B, Freedman J, Mohan SV. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jan 7;384(1):20-30. doi: 10.1056/NEJMoa2030340. Epub 2020 Dec 17.
• Soin AS, Kumar K, Choudhary NS, Sharma P, Mehta Y, Kataria S, Govil D, Deswal V, Chaudhry D, Singh PK, Gupta A, Agarwal V, Kumar S, Sangle SA, Chawla R, Narreddy S, Pandit R, Mishra V, Goel M, Ramanan AV. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Respir Med. 2021 May;9(5):511-521. doi: 10.1016/S2213-2600(21)00081-3. Epub 2021 Mar 4.

Helpful Links

• WHO Coronavirus (COVID-19) Dashboard
• A minimal common outcome measure set for COVID-19 clinical research
• Clinical Spectrum COVID 19
• McCullagh P. Regression Models for Ordinal Data [Internet]. Vol. 42, Journal of the Royal Statistical Society: Series B (Methodological). 1980. p. 109-27.
• Williams R. Understanding and interpreting generalized ordered logit models [Internet]. Vol. 40, The Journal of Mathematical Sociology. 2016. p. 7-20
• Ordered Logistic Regression | Stata Annotated Output
• Brant R. Assessing proportionality in the proportional odds model for ordinal logistic regression. Biometrics [Internet]. 1990 Dec;46(4):1171-8.
• A Proportional Hazards Model for the Subdistribution of a Competing Risk Jason P. Fine &Robert J. Gray
• Ho DE, Imai K, King G, Stuart EA. Matching as Nonparametric Preprocessing for Reducing Model Dependence in Parametric Causal Inference [Internet]. Vol. 15, Political Analysis. 2007. p. 199-236.
• Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies [Internet]. Vol. 34, Statistics in Medicine. 2015. p.
• Matschinger H, Heider D, König H-H. A Comparison of Matching and Weighting Methods for Causal Inference Based on Routine Health Insurance Data, or: What to do If an RCT is Impossible. Gesundheitswesen [Internet]. 2020 Mar;82(S 02):S139-50.
• Interleukin-6 Inhibitors
• COVID 19 Rapid Guideline managing COVID 19
• ACTUALIZACIONES BASADAS EN EVIDENCIA COVID-19 Tocilizumab para el tratamiento de pacientes con COVID-19
• IDS COVID 19 guideline treatment and management
• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Anticipated): July 1, 2021
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: June 10, 2021
• First Submitted That Met QC Criteria: June 10, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Actual): June 14, 2021
• Last Update Submitted That Met QC Criteria: June 10, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: covid 19; tocilizumab; severe pneumonia
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia
• Other Study ID Numbers: 6052 (CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No