Mixed bag of IL-6 inhibitor in severe COVID-19

Discussions on the use of interleukin-6 inhibitors, including tocilizumab (Actemra) and sarilumab (Kevzara), in COVID-19 patients may continue. Improved survival.

In COVACTA trialNo significant difference in clinical status or mortality after 28 days between tocilizumab and inpatients with severe COVID-19 pneumonia randomized to standard treatment only, sponsored by tocilizumab manufacturer Roche And Baylor’s Ivan Rosas, MD reported the School of Medicine in Houston, and colleagues, early editions New England Journal of Medicine..

But practical and government-funded REMAP-CAP trialAccording to Anthony C. Gordon et al. Of Imperial College London, the survival rate of patients assigned to tocilizumab or sarilumab was improved by about 70% compared to standard care alone. Write again NEJM..

The latter is consistent with the UK-based RECOVERY trial, another practical trial of COVID-19, with a slight but significant mortality benefit in severely ill COVID-19 patients. It was. Announced in press release afterwards Published as preprint data on medRxiv..

Ann Ancillary editorial Along NEJM Editor-in-chief Eric Rubin, MD and colleagues noted the differences between the COVACTA and REMAP-CAP exams and RECOVERY. These included enrollment criteria, time when anti-IL-6 therapy was started, primary outcome, and background care.

The most important variable they pointed out was the standard treatment accepted when the trial was conducted.

“One of the most notable changes is that patients with severe illness … are now almost universally given glucocorticoids,” the editors write. 19% of COVACTA tocilizumab patients and 29% of placebo patients received glucocorticoids, whereas 93% of REMAP-CAP patients and 82% of RECOVERY patients received glucocorticoids.

COVACTA

Rosas et al. Conducted COVACTA, a phase III international randomized trial in patients at 62 hospitals in nine countries in Europe and North America, including the United States, from April 3 to May 28, 2020. did. Participants were adults hospitalized with severe COVID. 19 Randomized 2: 1 to administer either pneumonia, tocilizumab or placebo, and a quarter of participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. It was.

The primary outcome is 28 on a sequential scale ranging from 1 (discharge or preparation for discharge) to 7 (death) in the modified treatment intent population, including patients who received at least one dose of either tocilizumab or placebo. It was the clinical condition of the day.

Overall, 438 patients were included in this population-294 in the intervention group and 144 in the placebo group. Of these, 65 patients received a second dose of tocilizumab and 43 received a second dose of placebo. The average age was about 61 years in both groups, with about 70% of patients being male and 53% to 60% of patients being Caucasian. Fewer patients in the tocilizumab group received glucocorticoids at baseline and during the study compared to the placebo group.

Mean clinical status on normal scale on day 28 was 1.0 for intervention and 2.0 for placebo (defined as non-ICU hospitalization without oxygen supplementation). They should not use the odds ratio for statistical comparisons because the pre-specified point estimate of the therapeutic effect on the primary outcome is the odds ratio and “the assumption of proportional odds is not met in this group”. Said.

The difference in mortality on day 28 was also not significant (19.7% for intervention vs. 19.4% for placebo), but the authors stated that no trials were conducted for this result.

Examining safety, adverse events were similar between groups (34.9% with intervention vs. 38.5% with placebo).

The authors pointed to the potential benefits of tocilizumab until discharge or stay in the ICU, but both said further research was needed.

One of the potential limitations to the data was the lack of standardized treatment sites and across the country, and “the wide range of possible interactions with antivirals and glucocorticoids.”

REMAP-CAP

Adult patients with COVID-19 receiving respiratory or cardiovascular support in the ICU were assigned with REMAP-CAP to receive either tocilizumab, sarilumab, or placebo in addition to regular care. .. The main results were respiratory and cardiovascular organ-free days using an ordinal scale from in-hospital death (-1) to day 21 without organ support.

These data have been collected since April 19, 2020, and on October 28, an independent data and safety oversight committee discovered that tocilizumab meets statistical criteria for efficacy.

At the time of the study, 353 patients were assigned to tocilizumab, 42 were assigned to sarilumab, and 402 were assigned to controls. They said standard treatment included glucocorticoids in more than 80% of patients.

The median number of days free of organ support was 10 days in the tocilizumab group, 11 days in the sarilumab group, and 0 days in the control group. Gordon et al. State that an odds ratio greater than 1 “indicates improved survival, increased days without organ support, or both.” The median adjusted cumulative odds ratio was 1.64 (95% CI 1.25-2.14) for tocilizumab and 1.76 (95% CI 1.17-2.91) for sarilumab.

The pooled IL-6 group had an in-hospital mortality rate of 27%, compared to 36% in the control group, with a median adjusted odds ratio for in-hospital survival of 1.64 (95% CI 1.14-2.35) for tocilizumab. It was 2.01 (95% CI 1.18). -4.71) For sarilumab.

Nine serious adverse events were reported in the tocilizumab group, including five bleeding events, and 11 serious adverse events were reported in the control group. No serious adverse events have been reported with sarilumab.

Given the two “different outcomes” of the trial, Rubin and his colleagues concluded in an editorial: [IL-6] Inhibitors, at least in some circumstances, but how they are used remains unclear. “