Treating COVID-19 with tocilizumab (a medicine that blocks interleukin-6) reduces the numbers of people who die within 28 days of treatment, and probably results in fewer serious unwanted effects than placebo treatment.
Studies of other medicines that block interleukin-6 to treat COVID-19 are under way. We will update this review when results from them become available.
COVID-19 is an infectious respiratory disease caused by a type of virus called a coronavirus. If the infection becomes severe, people may need intensive care and support in hospital, including machines to help them breathe (mechanical ventilation). Medicines that are currently used to treat other diseases are being tested in the search to find effective treatments for COVID-19.
An immune response is how the body recognises and defends itself against harmful substances, such as viruses. COVID-19 can disrupt the immune system, causing it to over-react and produce dangerously high levels of inflammation. Interleukin-6 (IL-6) is a protein involved in triggering inflammation. Blocking the production of interleukin-6 could reduce inflammation and help the immune system to fight COVID-19.
Why we did this Cochrane Review
Tocilizumab and sarilumab are two medicines that block interleukin-6. They are used to treat other conditions that involve an "over-reactive" immune system, such as rheumatoid arthritis. We wanted to find out if medicines that block interleukin-6 can be used to treat COVID-19, and whether they might cause any unwanted effects.
What did we do?
We searched for studies that tested if medicines that block interleukin-6 could treat COVID-19.
We looked for randomised controlled studies, in which the treatments people received were decided by chance. This type of study usually gives the most reliable evidence about the effects of a treatment.
Search date: we searched for trials up to 26 February 2021.
What we found
We found 10 studies in 6896 people with COVID-19. The average age of people in the studies was 56 to 65 years, and 66% of the people enrolled were men. The studies took place in Brazil, China, France, Italy, the UK and the USA; four studies took place in more than one country. Three studies were funded by pharmaceutical companies.
The medicines tested were tocilizumab and sarilumab. Both medicines were compared against a placebo (a dummy treatment that appears identical to the medicine being tested but without any active medicine) or standard care. The results were measured 28 days after treatment and after 60 days or more.
We also found 41 more studies of medicines blocking interleukin-6 to treat COVID-19 that had not yet published any results. These included 20 studies of tocilizumab, 11 studies of sarilumab and 10 studies of other medicines. Some of those studies are still ongoing and we will update this review to include their results when published.
What are the main results of our review?
Compared with placebo treatment or standard treatment, treatment with tocilizumab:
· reduces the number of people who died, of any cause, after 28 days (evidence from 6363 people in 8 studies); on average, 32 fewer people per 1000 died when treated with tocilizumab plus standard care, compared with standard care alone or placebo.
· probably makes little or no difference to clinical improvement (which is defined as leaving hospital or improvement in COVID-19 symptoms) at 28 days (evidence from 5585 people in 7 studies).
· probably reduces slightly the number of serious unwanted effects, such as life-threatening conditions or death (evidence from 2312 people in 8 studies).
We are uncertain about the effects of tocilizumab treatment on:
- severity of COVID-19; that is, how many patients died of COVID-19 or needed a ventilator or additional organ support at 28 days (evidence from 712 people in 3 studies); or
- how many patients died, of any cause, after 60 days or more (evidence from 519 people in 2 studies).
No results were reported for tocilizumab after 60 days or more for improvement, or severity at 28 days of COVID-19.
We are uncertain about how sarilumab treatment affected the:
- numbers of people who died (of any cause) at 28 days (evidence from 880 people in 2 studies) and after 60 days (evidence from 420 people in 1 study); or
- the numbers of serious unwanted effects, such as life-threatening conditions or death (evidence from 880 people in 2 studies).
- Sarilumab probably does not cause more unwanted effects (of any type) than placebo treatment (evidence from 420 people in 1 study). No other results for sarilumab treatment were reported.
We were not able to explore which COVID-19 patients are more likely to benefit from this treatment.
Our confidence in our results
We are confident that tocilizumab reduced the number of deaths (from any cause) at 28 days. Our confidence in the other results for tocilizumab is moderate to low; further evidence may change our results. Our confidence in the results for sarilumab is low; further evidence is likely to change these results. Our confidence was lowered because some of the studies did not report all their results.
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).
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.
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.
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.
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.
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.
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.