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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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.
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.
- Tocilizumab (Actemra®/RoActemra®; Hoffman La Roche Ltd) and sarilumab (Kevzara®; Sanofi-Genzyme) are monoclonal antibodies (mAbs) that target both the soluble and membrane-bound forms of the human IL-6 receptor (anti-IL-6R mAbs).
- On January 7, 2021, investigators from the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) issued a preprint reporting pronounced clinical benefit for both tocilizumab and sarilumab when given to critically ill patients requiring ICU care, including improved organ support free days and survival (mortality reduced by 24%; 35.8% for standard of care, 27.3% in the pooled treatment group). Greatest treatment effects were observed in patients treated with both an IL-6R antagonist (tocilizumab or sarilumab) and corticosteroids (fixed dose or shock-dependent). No increase in serious adverse events were observed in patients receiving tocilizumab or sarilumab compared to treatment with standard of careFootnote 1.
- On February 11, 2021, the UK-based randomized open-label RECOVERY trial issued a preprint on the preliminary results of their tocilizumab treatment arm (n=4116)Footnote 2. Trial investigators reported clinical benefit for tocilizumab when given to hospitalized patients with evidence of hyperinflammation and hypoxia, including reduced mortality (14% risk reduction; 33% for standard of care, 29% in the tocilizumab group) and the composite endpoint of invasive mechanical ventilation or death (15% risk reduction; 38% for standard of care, 33% for tocilizumab). Greatest treatment effects were observed in patients treated with both tocilizumab and systemic corticosteroids. No increase in serious adverse events were observed in patients receiving tocilizumab compared to treatment with standard of care. However, these preliminary results have not been peer reviewed.
- Earlier randomized controlled trials (RCTs) have reported mixed clinical outcomes associated with use of therapeutics targeting the IL-6 receptor to treat patients with COVID-19. These trials varied in terms of inclusion criteria for disease severity as well as timing of treatment, suggesting that the results observed in REMAP-CAP may reflect either a requirement for a very select population and administration window in order for the drugs to be effective, or bias and confounding of the trials.
Clinical evidence of efficacy to date
- On January 7, 2021, investigators from the REMAP-CAP trial issued a preprint (not peer reviewed) on preliminary findings from their tocilizumab and sarilumab treatment arms (see post-hoc statement)Footnote 1. Patients were randomized to receive sarilumab (400 mg single IV injection; n=48), tocilizumab (8mg/kg up to 800mg IV injection with option to repeat 12-24h later; n=353) or control (n=402). All patients received site-specific standard of care, which included corticosteroids for over 80% of participants, and remdesivir for 32.8% of participants. Hospital mortality was 28.0% (98/350) for the tocilizumab group, 22.2% (10/45) for the sarilumab group and 35.8% (142/397) for the control group. The median adjusted odds ratio for survival was 1.64 (95% credible interval, 1.14-2.35) and the Bayesian probability of superiority were 99.6% for tocilizumab, and were 2.01 (95% credible interval, 1.18-4.71) and 99.5% for sarilumab compared with control. Secondary treatment effects included reduced time to ICU discharge for both treatments [tocilizumab median OR 1.42 (95% CrI 1.18 to 1.70), sarilumab median OR 1.64 (95% CrI 1.21 to 2.45) versus control]. Treatment effect was enhanced when corticosteroids (both fixed-dose and shock-dependent) were administered in addition to tocilizumab and sarilumab; however, data on the number of patients given concomitant corticosteroids in the trial groups were not provided. Limitations to this trial include the open-label design, which introduces additional risks of bias, and a highly selected population (3301 patients screened and only 895 randomized). While the REMAP-CAP is a multicentre trial, centres chose which treatment arms to participate in, but all included a control arm. Thus, not all centres would be represented equally in each arm and the sarilumab arm had very few patients compared tocilizumab arm. This could lead to unknown confounders (e.g., differences in standards of care at different sites) contributing to observed differences, which were adjusted for in the primary analytic Bayesian model. The primary analysis used a Bayesian hierarchical model with a “nested analysis” of both IL-6R antagonists. When their data emerged as similar, the model employed dynamic borrowing to allow conclusions for both drugs. This analysis methodology may reduce the impact of limited enrollment in the sarilumab arm. Sufficient information is not provided on how the composite ordinal primary outcome (number of respiratory and cardiovascular organ support-free days up to day 21) is converted to a dichotomous variables to provide an odds ratios.
- On December 17, 2020, Salama et al. published their findings from the Roche-sponsored multinational Evaluating Minority Patients with Actemra® (EMPACTA) trialFootnote 3. Adult patients hospitalized with COVID-19 pneumonia were randomized to receive either IV tocilizumab 8mg/kg, ≤ 800mg, or placebo, both in addition to standard of care (n=377 in the intention-to-treat population). The majority of patients were of Hispanic ethnicity. The authors reported hospitalized adult patients with COVID-19 pneumonia who received tocilizumab were less likely to progress to mechanical ventilation or death by day 28, compared to patients who received placebo plus standard of care (12.0% vs. 19.3%; log-rank p= 0.04; HR = 0.56; 95% CI 0.33 to 0.97). There was no significant difference in the median time to hospital discharge or readiness for discharge (HR 1.16; 95% CI, 0.91 to 1.48) and the median time to improvement in clinical status assessed based on 7-category ordinal scale (HR, 1.15; 95% CI, 0.90 to 1.48) over the 28-day period. This 7-category ordinal scale is an unvalidated measure of disease severity in COVID-19, and is similar to an unvalidated 8-category ordinal scale used in the ACTT-1 trial that evaluated the use of remdesivir in COVID-19Footnote 4. While ACTT-1 showed an improvement in the unvalidated ordinal scale with remdesivir, which led to its authorization for use in COVID-19, neither ACTT-1 nor the subsequent WHO-sponsored SOLIDARITY trial demonstrated a mortality benefitFootnote 4Footnote 5. Similar results are seen here, with statistically significant improvement in an unvalidated scale but no statistically significant difference in mortalityFootnote 3. Unvalidated measures of disease severity should be interpreted with caution.
- On October 20, 2020, two open-label randomized clinical trials published their findings in JAMA Internal Medicine, reporting no statistically significant difference in mortality or significant clinical benefit in association with tocilizumab as a treatment for hospitalized patients with either severe COVID-19 pneumonia characterized by acute respiratory failureFootnote 6 or moderate to severe COVID-19Footnote 7. Both these studies excluded patients admitted to ICU for care, patients receiving invasive mechanical ventilation, and patients receiving non-invasive mechanical ventilation at the time of randomizationFootnote 6Footnote 7. It is unclear if the differences observed in the mortality results of these trials as compared to REMAP-CAP is due to differences in population and study design (e.g., treatment timing or disease severity, or differences in how the primary outcomes were measured), or bias/confounding in any of the three trialsFootnote 1Footnote 6Footnote 7.
- On September 12, 2020, Rosas et al. released a preprint of the Roche-led trial. The findings were later verified in a peer-reviewed publication (see post-hoc statement)Footnote 8. The trial evaluated tocilizumab in hospitalized adult patients with severe COVID-19 pneumonia with blood oxygen saturation ≤93% or partial pressure of oxygen/fraction of inspired oxygen <300 mm/Hg (n=438)Footnote 9. Patients were randomized 2:1 to receive either IV tocilizumab [8mg/kg, ≤ 800mg] or placebo plus standard of care; multi-national). The authors reported no significant differences between the tocilizumab arm and the placebo arm in the single primary outcome of clinical status as assessed on a 7-category ordinal scale at day 28 (median score 1.0 vs. 2.0; p=0.31). Subgroup analyses based on clinical severity at baseline also failed to show statistical differences for this outcome. Although the trial failed to reach the primary endpoint, some clinical benefit was attributable to the treatment. Median time to hospital discharge was significantly shorter in the tocilizumab arm than in the placebo arm (20.0 days [95% CI 17.0-27.0] vs. 28.0 days [95% CI 20.0-not evaluable], respectively; HR 1.35 [95% CI 1.02–1.79]). In a subgroup analysis of patients not in ICU at baseline, the incidence of ICU admission was significantly lower in the tocilizumab arm than in the placebo arm (21.3% [ 27/127] vs. 35.9% [ 23/64]; weighted difference: –14.8% (95% CI – 28.6 to –1.0). Among patients not on mechanical ventilation at baseline, the proportion of patients who reached clinical failure (defined as death, withdrawal from the study during hospitalization, transferred to ICU, or requirement for invasive mechanical ventilation within 28 days of baseline) was significantly lower in the tocilizumab arm than in the placebo arm (29.0% [53/183] vs. 42.2% [38/90]; HR 0.614 [95% CI 0.40 to 0.94]).
- In a network meta-analysis on five randomized controlled trials comparing tocilizumab to placebo treatment in patients with mild/moderate/severe/critical COVID-19 (n=1336 patients total)Footnote 6Footnote 7Footnote 8Footnote 9Footnote 10Footnote 11, the unfavorable risk ratio of incidence of all-cause mortality from days 14-28 was 1.09 (95% CI 0.80 to 1.50)Footnote 12. This association was graded as moderate certainty of evidence due a wide confidence intervalFootnote 12. Two of the five included trials limited their enrolment to patients with severe COVID-19 (n=192 patient total out of 1336 included in the meta-analysis); neither had statistically significant treatment effects for this outcome when considered as individual trialsFootnote 6Footnote 11.
- On September 1, 2020, Sanofi released a media statement reporting the results from their RCT testing sarilumab in hospitalized adult patients with COVID-19 who may require ICU care (n=420 patients enrolled and randomized to receive either sarilumab IV at 200 or 400mg doses or placebo, both in addition to standard of care)Footnote 13. The authors reported no significant differences in time to improvement of two points or greater on a 7-point clinical scale or in percentage of patients alive at day 29 (data not released). The media report stated that treatment with sarilumab led to a numerical decrease in the duration of hospital stay as well as an acceleration in the time to improve clinical outcomes, as measured by a 2-point improvement from baseline on the aforementioned 7-point scale. While the trial did not report a survival benefit in the overall population, the press release reported a trend toward reduced mortality in patients critically ill with COVID-19. Actual treatment effects were not reportedFootnote 13.
- On April 27, 2020 and July 2 2020, Regeneron issued press releases on their Phase 2/3 trial testing Kevzara® (Sarilumab, 200 or 400mg single IV injection) in hospitalized patients with COVID-19Footnote 14Footnote 15. Preliminary findings from the Phase 2 portion of their trial indicated clinical benefit was specific to patients with critical illness, defined as patients requiring mechanical ventilation or high-flow oxygenation or treatment in ICUFootnote 14. The trial’s independent data monitoring committee recommended a protocol amendment for the Phase 3 portion of the trial to restrict patient enrolment to critical illness and limit dosing to 400mg. Trial sponsors later announced the Phase 3 portion of the trial (n=194 patients receiving mechanical ventilation at time of enrolment) did not meet its primary and key secondary endpointsFootnote 15. While no data were provided, the media report noted minor positive trends in patients who were on mechanical ventilation at baseline that were countered by negative trends in patients who were not, including the proportion of patients who died by day 29Footnote 15. These findings have not been released in a preprint or published in a peer-reviewed paper. Unlike the REMAP-CAP trialFootnote 1, the sarilumab trial did not specify timing of treatment relative to initiation of respiratory support. It is unclear if the differences observed in the mortality results of these trials as compared to REMAP-CAP reflect differences in population and study design (e.g., treatment timing or disease severity, or differences in how the primary outcomes were measured), or bias/confounding in any of the three trialsFootnote 1Footnote 13Footnote 14Footnote 15.
Clinical evidence of safety to date
- The safety profiles of both tocilizumab and sarilumab, when used for the indication of rheumatoid arthritis (RA), are well documented. For this indication, the most frequent serious adverse events (SAEs) for both tocilizumab and sarilumab were serious infections, notably pneumonia and cellulitisFootnote 16Footnote 17. The most common adverse reactions that required discontinuation of tocilizumab therapy were increased hepatic transaminase values (per protocol requirement) and serious infections (tocilizumab)Footnote 16, and neutropenia and elevated ALT levels (sarilumab)Footnote 17.
- These products have not been authorized by Health Canada for the indication of COVID-19, thus this use would be off-label. The Health Canada-approved product monographs for Actemra® and Kevzara®, issued by Roche and Sanofi Canada respectively, both state that treatment with their anti-IL-6R mAb should not be initiated in patients with active infections, including chronic or localized infectionsFootnote 16Footnote 17.
- In a network meta-analysis on eight randomized controlled trials comparing tocilizumab to placebo in patients with mild/moderate/severe/critical COVID-19 (n=2312 patients total)Footnote 6Footnote 7Footnote 8Footnote 9Footnote 10Footnote 11Footnote 18Footnote 19Footnote 20, the risk ratio of incidence of serious adverse events was 0.89 (95% CI 0.75 to 1.06)Footnote 12. This association was graded as moderate certainty of evidence due to a wide confidence interval with the possibility for no effect and the possibility for harmFootnote 12.
- The REMAP-CAP trial, which was not included in the meta-analysis above, reported no safety signals. The frequency of patients reporting ≥1 serious adverse events was reported as 2.5% (9/353 patients) in the tocilizumab group, 0% (0/48 patients) in the sarilumab group, and 2.7% (11/402 patients) in the placebo groupFootnote 1. While the rate of infections and serious infections was similar in the trial groups in the Roche-sponsored Phase 3 COVACTA RCT assessing tocilizumab in hospitalized adult patients with severe COVID-19, bleeding events, hypersensitivity, and hepatic events were more common in the tocilizumab arm. No p-values were provided in the pre-print; thus, the statistical significance of these findings is unknownFootnote 9. In the Sanofi-sponsored Phase 3 RCT assessing sarilumab in hospitalized adult patients with COVID-19, SAEs were experienced by 26-29% of patients treated with sarilumab and 24% of patients given the placebo. No increase of incidence of serious infections was observed for patients receiving sarilumabFootnote 13.
- Observational data evaluating the safety of these drugs in COVID-19 include:
- Safety signals reported in observational cohort studies on tocilizumab in patients with COVID-19 included increased incidence of secondary infectionsFootnote 21Footnote 22Footnote 23. Tocilizumab treatment was associated with significant increases in transitory neutropeniaFootnote 24, new infectionsFootnote 22, and more bacteremiaFootnote 23, all compared to standard of care alone. However, these accounts are based on non-interventional studies and therefore are not conclusive evidence of safety signals attributed to tocilizumab or sarilumab, respectively, in COVID-19 patients.
- Other sources: In a systematic review and meta-analysis assessing the efficacy of tocilizumab in addition to standard of care for COVID-19, the rate of secondary infection was numerically higher (but not statistically significant) for the tocilizumab group [RD: 0.10; 95%CI (-0.01 to 0.20), p-value = 0.07)Footnote 25. The CADTH review of evidence on tocilizumab for COVID-19 concluded that the clinical evidence at the time of publication was inconsistent with respect to occurrence of SAEs for tocilizumab comparted to no tocilizumabFootnote 26. This publication preceded clinical data released from the two Roche-sponsored Phase 3 trials, neither of which report drug attributable safety signals, but their findings have not yet been published in a peer-reviewed journal.
Authorization/licensure status in Canada
- Tocilizumab (Actemra®/RoActemra®, Roche) is authorized by Health Canada for the following indications: RA (IV or subcutaneous (SC) formulation), giant cell arteritis (SC formulation), polyarticular juvenile idiopathic arthritis (IV or SC formulation), systemic juvenile idiopathic arthritis (IV or SC formulation), and cytokine release syndrome (IV formulation)Footnote 16.
- Sarilumab (Kevzara®, Sanofi-Genzyme, SC formulation only) is authorized by Health Canada for the treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more biologic or non-biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs)Footnote 17.
- The REMAP-CAP trial provides evidence of a clinical benefit for early treatment with tocilizumab or sarilumab when administered to adults hospitalized for the treatment of severe COVID-19 with recent (<24h) requirement for respiratory/cardiovascular organ supportFootnote 1.
- Subgroup analyses of the REMAP-CAP trial suggest i) treatment effects for both tocilizumab and sarilumab are maximal when combined with corticosteroids, and ii) treatment effects and patient age may be inversely associated, where younger persons (aged 18 to 39 years) demonstrated greater treatment effectsFootnote 1.
- Children aged 18 and under were excluded from the REMAP-CAP trialFootnote 1. Tocilizumab is approved in Canada for use in patients aged 2 and over while sarilumab is approved for patients aged 18 and over. Efficacy of sarilumab has not been studied in children less than 18 years of ageFootnote 17.
- Pregnant women were excluded from the REMAP-CAP trialFootnote 1. Both tocilizumab and sarilumab have limited data on their safety during pregnancy, and manufacturers state "women of childbearing potential must use effective contraception during and up to 3 months after treatment”Footnote 16,Footnote 17.
- Taking the REMAP-CAP results in context with previously reported RCTs on tocilizumab and sarilumab for off-label use in the treatment of COVID-19, the trials exhibited high levels of heterogeneity regarding inclusion criteriaFootnote 1Footnote 3Footnote 6Footnote 7Footnote 8Footnote 9Footnote 10Footnote 11Footnote 12Footnote 13Footnote 14Footnote 15. There remains limited evidence to determine specific COVID-19 patient populations where treatment with an anti-IL-6R mAb may have a positive benefit to risk ratio. This may become a logistical challenge in the clinical setting, with rising cases of COVID-19 in Canada, and a likely limited supply of these drugs available, which may lead to limited access to COVID-19 patients and/or drug shortages for approved indications and ongoing use in patients using them for chronic indications.
- Several safety signals have emerged in COVID-19 patients following treatment with a mAb targeting the IL-6R, including increased secondary infections and neutropeniaFootnote 21Footnote 22Footnote 23Footnote 24Footnote 25, consistent with precautions and contraindications established in the product monographsFootnote 16Footnote 17.
- Emphasis is placed on a physician’s careful consideration for any off-label use of tocilizumab or sarilumab. For the treatment of COVID-19, clinical evidence suggests survival benefit may be limited to a narrow treatment window in a specific patient population as per the specific indication and treatment timing articulated in this recommendation.
Post-hoc statement issued March 2, 2021
- Emergent (not yet peer reviewed) evidence from the RECOVERY trialFootnote 2 is supportive of the results from the REMAP-CAP trial, and suggests treatment with tocilizumab may be beneficial to a larger patient population as indicated by evidence of hypoxia and hyperinflammation. The clinical findings from this and other studies will be considered for future recommendations following peer-reviewed publication.
- On February 25, 2021; the Roche-sponsored COVACTA trial on tocilizumab in hospitalized patients published their clinical findings in a peer-reviewed journalFootnote 8; the interpretation of the clinical trial has not changed from the original preprintFootnote 9.
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
- 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
- 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
- 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
- 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
- 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.
- 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.
- 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.
- Footnote 8
Rosas et al., Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. NEJM. 2021 Feb 25; DOI: 10.1056/NEJMoa2028700
- Footnote 9
Rosas, I., et al., Tocilizumab in Hospitalized Patients with COVID-19 Pneumonia. medRxiv, 2020: doi: 10.1101/2020.08.27.20183442
- 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.
- Footnote 11
Salama, C., et al., Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia. medRxiv, 2020: doi: 10.1101/2020.10.21.20210203
- 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
- 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
- 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
- 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
- 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.
- 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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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