Tocilizumab and Sarilumab, Interleukin‐6 blocking (IL-6) agents for treating COVID‐19:

Drug treatment for Covid-19 is evolving rapidly. The living guideline by the WHO/BMJ group is one of the key guidance to this rapidly changing crucial topic for Covid-19 patient care. The current version was published on 6 July 2021

There has been increasingly strong recommendation of Interleukin‐6 blocking agents (IL-6) for treating COVID‐19 even by the WHO. Tocilizumab and Sarilumab are extremely expensive medications approved for use in Covid-19 by the WHO in 2021 July.

The WHO based its recommendation mainly on two studies – LINK

The FDA recommendations of IL-6 blocking agent Sarilumab has even recommended for the use in primary care. There is a web report  that at least one RCT that tested Sarilumab was stoped because it did not meet the outcome measures.

In Sri Lanka Tocilizumab is available and a single dose varies between Rs 130,000 and 150,000 in the private sector. Tocilizumab is also available in MoH hospitals.

The objective of this post is to look into the fine details underlaying such strong recommendations for extremely expensive IL-6 inhibitors

 

Furthermore the low cost drugs for Covid-19, with a very long history of use in other diseases worldwide, such as Ivermectin is recommended only in research settings by the WHO.  

 

 


Latest from UpToDate

Monoclonal antibody therapy – Monoclonal antibodies that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to be evaluated in outpatients with mild to moderate disease, and trial results suggest a benefit from these agents [86-88]. In the United States, the following monoclonal antibody therapies are available through emergency use authorization (EUAs) for select outpatients at risk for severe disease ():

Casirivimab-imdevimab (600-600 mg, administered as a single IV dose [preferred], although may be given subcutaneously if IV not feasible or would delay treatment)

Sotrovimab (500 mg, administered as a single IV dose)

Tocilizumab and sarilumab alone or in combination with corticosteroids for COVID-19: A systematic review and network meta-analysis

Authors from: McMaster University, Harvard University, University of Oslo, University of Calgary

LINK

Abstract

Objective To compare the effects of interleukin-6 (IL-6) receptor blockers, with or without corticosteroids, on mortality in patients with COVID-19.

Design Systematic review and network meta-analysis

Data sources WHO COVID-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses

Study selection Trials in which people with suspected, probable, or confirmed COVID-19 were randomized to IL-6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care.

Results We assessed the risk of bias of included trials using a modification of the Cochrane risk of bias tool. We performed a Bayesian fixed effect network meta-analysis and assessed the certainty of evidence using the GRADE approach.

We identified 45 eligible trials (20,650 patients), 36 (19,350 patients) of which could be included in the network meta-analysis. 27 of 36 trials were rated at high risk of bias, primarily due to lack of blinding. Tocilizumab (20 more per 1000, 15 fewer to 59 more; low certainty) and sarilumab (11 more per 1000, 38 fewer to 55 more; low certainty) alone may not reduce the risk of death. Tocilizumab, in combination with corticosteroids, probably reduces the risk of death compared to corticosteroids alone (35 fewer per 1000, 52 fewer to 18 more; moderate certainty) and sarilumab, in combination with corticosteroids, may reduce the risk of death compared to corticosteroids alone (43 fewer, 73 fewer to 12 more; low certainty). Tocilizumab and sarilumab, both in combination with corticosteroids, may have similar effects (8 more per 1000, 20 fewer to 35 more; low certainty).

Conclusion IL-6 receptor blockers, when added to standard care that includes corticosteroids, in patients with severe or critical COVID-19, probably reduce mortality. Tocilizumab and sarilumab may have similar effectiveness.

Systematic review registration NA

What is already known on this topic?

  • IL-6 receptor blockers have immunosuppressive effects that may be important in COVID-19 patients with immune system dysfunction and inflammation

  • Corticosteroids reduce the risk of death in patients with severe or critical COVID-19

What this study adds

  • Our systematic review and network meta-analysis provides a comprehensive review of the evidence addressing the effects of IL-6 receptor blockers, alone or in combination with corticosteroids, in COVID-19

  • IL-6 receptor blockers when added to a standard care that includes corticosteroids, in patients with severe or critical COVID-19, probably reduce mortality.

  • Tocilizumab and sarilumab in combination with corticosteroids may have similar effectiveness for reducing mortality.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

Funding: This project is supported by two CIHR Operating Grants (VR4- 172738; MM1- 174897).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRB exempt. All data secondary.

All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

WHO July 6 Recommendation References – for the current Magic Guideline

  1. Tocilizumab and sarilumab alone or in combination with corticosteroids for COVID-19: A systematic review and network meta-analysis (in MedRxiv server not published, posted on July 7) LINK
  2. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19A Meta-analysis. JAMA 2021 July 6 LINK
  3. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. NEJM 2021 Feb 11 LINK 
  4. NIH – COVID-19 Treatment Guidelines LINK

 


Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19A Meta-analysis

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group
JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330
Abstract

Importance  Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.

Objective  To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

Data Sources  Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.

Study Selection  Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.

Data Extraction and Synthesis  In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.

Main Outcomes and Measures  The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.

Results  A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

Conclusions and Relevance  In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Interleukin‐6 blocking agents for treating COVID‐19: a living systematic review

Authors from: Cochrane France, Cochrane Germany, Cochrane Denmark, Cochrane Ireland, Cochrane Chile 

LINK

Abstract

Background

Interleukin 6 (IL‐6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID‐19). Their immunosuppressive effect might be valuable in patients with COVID‐19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance.

Objectives

To assess the effect of IL‐6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID‐19.

We will update this assessment regularly.

Search methods

We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L‐OVE platform, and Cochrane COVID‐19 Study Register to identify trials up to 26 February 2021.

Selection criteria

We included randomised controlled trials (RCTs) evaluating IL‐6 blocking agents compared with standard care alone or with placebo for people with COVID‐19, regardless of disease severity.

Data collection and analysis

We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/‐ additional organ support OR death) (D28 / ≥ D60); all‐cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events.

Main results

We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer‐reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants).

All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi‐country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline.

We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple‐arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three‐arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison.

Tocilizumab versus standard care alone or with placebo

a. Effectiveness of tocilizumab for patients with COVID‐19

Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate‐certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer‐term follow‐up (≥ D60).

The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low‐certainty evidence). We did not obtain data for longer‐term follow‐up (≥ D60).

Tocilizumab reduces all‐cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high‐certainty evidence). There is uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low‐certainty evidence).

b. Safety of tocilizumab for patients with COVID‐19

The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low‐certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate‐certainty evidence).

Sarilumab versus standard care alone or with placebo

The evidence is uncertain about the effect of sarilumab on all‐cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all‐cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded

No data were available for other critical outcomes.

Authors’ conclusions

On average, tocilizumab reduces all‐cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist‐defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta‐analyses are needed to be able to identify which patients are more likely to benefit from this treatment.

Evidence for an effect of sarilumab is uncertain and evidence for other anti‐IL6 agents is unavailable.

Thirty‐nine RCTs of IL‐6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID‐NMA platform (covid-nma.com).


Guidance from Key organizations re biologicals

WHO

NICE

CDC

Australia

This is the right side column for evidence links

Cochrane Review references

  1. Interleukin‐6 blocking agents for treating COVID‐19: a living systematic review. Cochrane Library. 2021 March 18 LINK