Ad-hoc COVID-19 Clinical Pharmacology Task Group: Statement on tocilizumab and sarilumab

Clinical Pharmacology Task Group (CPTG) meeting dates: September 18, 2020 and January 8, 2021.

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Policy question

The Public Health Agency of Canada asked the Ad-hoc COVID-19 Clinical Pharmacology Task Group (CPTG) for advice on whether known and potential benefits of tocilizumab and sarilumab outweigh known and potential risks in the treatment of hospitalized patients with severe COVID-19.

Recommendation

The Clinical Pharmacology Task Group recommends that early treatment with intravenous (IV) tocilizumab could be considered in addition to standard of care (e.g. dexamethasone at 6mg IV for 10 days, or equivalent glucocorticoid) for hospitalized adult patients with severe COVID-19 with a recent (<24h) requirement for respiratory and/or cardiovascular organ support, defined as requirement of high-flow supplemental oxygen, invasive/non-invasive mechanical ventilation, or intravenous infusion of any vasopressor or inotrope.

The recommendation is based on findings from the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP). The trial evaluated IV tocilizumab 8mg/kg (up to 800mg, maximum 2 doses 12-24h apart) or IV sarilumab (400mg single dose).

Sarilumab is only available in Canada as a solution for subcutaneous injection. The IV formulation of sarilumab should be limited to the clinical trial setting.

This guidance will be updated as peer-reviewed evidence emerges, particularly regarding risks and benefits in older age groups, for those with different clinical presentations, and for different subgroups such as comorbidities, ethnicity and age.

This recommendation was approved by the CPTG on January 11, 2021. The previous recommendation on the use of tocilizumab and other agents targeting the IL-6 receptor was last updated on November 2, 2020.

Background

Clinical evidence of efficacy to date

Clinical evidence of safety to date

Authorization/licensure status in Canada

Considerations

Post-hoc statement issued March 2, 2021

Acknowledgements

This statement was prepared by: N Forbes, E Sarwar, J Courtemanche, B Mitchelmore, S Ha, M Rieder, and M Salvadori, on behalf of the Clinical Pharmacology Task Group (CPTG).

CPTG Members: M Salvadori (Co-Chair), M Rieder (Co-chair), M Lordkipanidze, R Hall, M Piquette-Miller,

A Collier, J Kimmelman and S Murthy.

Note: S Murthy was excluded from deliberations on the CPTG recommendation statement given self-declared conflict of interest (affiliation with the REMAP-CAP trial).

CPTG gratefully acknowledges the contribution of S Gadient and C Marinsky.

CPTG also gratefully acknowledges the contribution from the Canadian Agency for Drugs and Technologies in Health (CADTH) and Institut National D'excellence en Santé et Services Sociaux (INESSS).

Approved by the Clinical Pharmacology Task Group on January 11, 2021

References Cited

Footnote 1

Gordon, C., et al., Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. medRxiv, 2021.01.07.21249390; doi: 10.1101/2021.01.07.21249390

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Footnote 2

Hornby et al., Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv., 11 February 2021. DOI: 10.1101/2021.02.11.21249258

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Footnote 3

Salama, C., et al., Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jan 7; 384(1):20-30. doi: 10.1056/NEJMoa2030340

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Footnote 4

Beigel, J.H., et al., Remdesivir for the treatment of Covid-19- Final Report. N Engl J Med. 2020 Nov 5; 383:1813-1826. doi: 10.1056/NEJMoa2007764

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Footnote 5

Pan, H., et al., Repurposed Antiviral Drugs for COVID-19- Interim WHO Solidarity Trial Results. N Engl J Med. 2020 Dec 2. doi: 10.1056/NEJMoa2023184.

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Footnote 6

Salvarani, C., et al., 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.

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Footnote 7

Hermine, O., et al., 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.

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Footnote 8

Rosas et al., Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. NEJM. 2021 Feb 25; DOI: 10.1056/NEJMoa2028700

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Footnote 9

Rosas, I., et al., Tocilizumab in Hospitalized Patients with COVID-19 Pneumonia. medRxiv, 2020: doi: 10.1101/2020.08.27.20183442

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Footnote 10

Stone, J.H., et al., Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Dec 10;383(24):2333-2344. doi: 10.1056/NEJMoa2028836.

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Footnote 11

Salama, C., et al., Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia. medRxiv, 2020: doi: 10.1101/2020.10.21.20210203

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Footnote 12

Nguyen, T.V., et. al for the COVID-NMA consortium., (2020). RCT studies on preventive measures and treatments for COVID-19 [Tocilizumab vs Standard care/Placebo]. Zenodo. https://covid-nma.com/living_data/index.php?comparison=28

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Footnote 13

Sanofi, Sanofi provides update on Kevzara® (sarilumab) Phase 3 trial in severe and critically ill COVID-19 patients outside the U.S. 2020 Sept 1. https://www.sanofi.com/en/media-room/press-releases/2020/2020-09-01-07-00-00

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Footnote 14

Regeneron, Regeneron and Sanofi Provide Update on U.S. Phase 2/3 Adaptive-Designed Trial of Kevzara® (Sarilumab) in Hospitalized Covid-19 Patients. 2020 Apr 27. https://newsroom.regeneron.com/index.php/news-releases/news-release-details/regeneron-and-sanofi-provide-update-us-phase-23-adaptive

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Footnote 15

Regeneron, Regeneron and Sanofi Provide Update on Kevzara® (Sarilumab) Phase 3 U.S. Trial in COVID-19 Patients. 2020 July 2. https://newsroom.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-update-kevzarar-sarilumab-phase-3

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Footnote 16

CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2016 [updated 2019 09 16; cited 2020 09 15]. ACTEMRA (tocilizumab) [product monograph]. Available from: http://www.e-cps.ca or http://www.myrxtx.ca. Also available in paper copy from the publisher.

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Footnote 17

CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2016 [updated 2019 08 08; cited 2020 09 15]. KEVZARA (sarilumab) [product monograph]. Available from:   http://www.e-cps.ca or http://www.myrxtx.ca. Also available in paper copy from the publisher.

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Footnote 18

Wang, D., et al., Tocilizumab Ameliorates the Hypoxia in COVID-19 Moderate Patients with Bilateral Pulmonary Lesions: A Randomized, Controlled, Open-Label, Multicenter Trial. Posted 2020 Aug 29. Available at SSRN: https://ssrn.com/abstract=3667681

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Footnote 19

The REMAP-CAP Investigators., Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. NEJM. 2021 Feb 25; doi: DOI: 10.1056/NEJMoa2100433

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Footnote 20

Veiga, C., 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 Jan 20. DOI: 10.1136/bmj.n84

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Footnote 21

Biran, N., et al., Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study. Lancet Rheumatol, 2020 Aug 14. 2(10): p. e603-e612. doi: 10.1016/S2665-9913(20)30277-0

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Footnote 22

Guaraldi, G., et al., Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol, 2020 June 24. 2(8): p. e474-e484. doi: 10.1016/S2665-9913(20)30173-9

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Footnote 23

Rojas-Marte, G., et al., Outcomes in patients with severe COVID-19 disease treated with tocilizumab: a case-controlled study. QJM, 2020 Aug 1. 113(8): p. 546-550. doi: 10.1093/qjmed/hcaa206

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Footnote 24

Campochiaro, C., et al., Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Intern Med, 2020 Jun. 76: p. 43-49. doi: 10.1016/j.ejim.2020.05.021

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Footnote 25

Aziz, M., et al., Efficacy of tocilizumab in COVID-19: A systematic review and meta-analysis. J Med Virol, 2020 Sept 12. doi: 10.1002/jmv.26509

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Footnote 26

Tocilizumab for the Treatment and Prevention of COVID-19: A Review of Clinical Effectiveness. Ottawa: 2020 Aug. (CADTH Technology Review).

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