Studies find mixed results for tocilizumab to treat COVID-19

Three studies recently published in JAMA Internal Medicine evaluated the effects of tocilizumab against COVID-19.

The studies were conducted in the United States, France and Italy, and all involved patients who were hospitalized with COVID-19.

In an editorial accompanying the studies, Jonathan B. Parr, MD, MPH, assistant professor of medicine in the division of infectious diseases at the University of North Carolina School of Medicine, wrote that the “newly released randomized trials suggest a potential role for tocilizumab in COVID-19 but do not show clear evidence of efficacy, in contrast to observational studies.”

Data on critically ill patients

In one study, David E. Leaf, MD, MMSc, assistant professor in renal disease at Harvard Medical School, and colleagues found that treatment with tocilizumab (Actemra, Genentech) within 2 days of ICU admission reduced the risk for in-hospital mortality among critically ill patients with COVID-19.

Leaf and colleagues used data from a multicenter cohort study of adults with COVID-19 who were admitted to the ICU at 68 U.S. hospitals from March 4 to May 10. Patients were followed until hospital discharge, death or through June 12.

The analysis included 3,924 patients, 11% of whom received tocilizumab within 2 days of ICU admission.

The researchers reported that severity of illness and other baseline characteristics were similar between the groups after applying inverse probability weighting.

Among participants, 39.2% died, including 28.9% of those who received tocilizumab and 40.6% of those who did not receive the agent.

Lead and colleagues determined that patients who were treated with tocilizumab had a lower risk for death compared with those who were not (HR = 0.71; 95% CI, 0.56-0.92) during a median follow-up period of 27 days.

The researchers estimated that the risk for 30-day mortality was 27.5% (95% CI, 21.2-33.8) among patients treated with tocilizumab and 37.1% (95% CI, 35.5-38.7) in patients who were not (risk difference = 9.6%; 95% CI, 3.1-16.0).

“The beneficial effect of tocilizumab on survival was particularly notable for those patients with a more rapid disease trajectory, defined as admission to the ICU within 3 days of symptom onset,” Leaf told Healio Primary Care. “In this group of patients, the mortality reduction with tocilizumab was 60%.”

He said he hopes the findings “will encourage and help inform the design of future randomized controlled trials to test the efficacy of tocilizumab, specifically among critically ill patients.”

Tocilizumab in patients with COVID-19, pneumonia

The two other studies examined the benefits of tocilizumab in patients with COVID-19 and pneumonia.

In a prospective, open-label, randomized clinical trial conducted at 24 hospitals in Italy, Carlo Salvarani, MD, of Unità Operativa di Reumatologia, and colleagues randomly assigned 126 patients with COVID-19-related pneumonia and a partial pressure of arterial oxygen to fraction of inspired oxygen ratio of 200 mm Hg to 300 mm Hg to receive either tocilizumab or standard care.

The 60 patients assigned to tocilizumab received the agent intravenously within 8 hours of randomization and another dose after 12 hours. The doses of tocilizumab ranged from 8mg/kg to 800 mg.

The 66 patients assigned to usual care received supportive care until their condition worsened, when they were then offered tocilizumab as a rescue therapy.

Salvarani and colleagues found that 28.3% of patients in the tocilizumab group and 27% of those in the standard care group experienced clinical worsening within 2 weeks of randomization (RR = 1.05; 95% CI, 0.59-1.86).

Among all participants, two from the tocilizumab group and one from the control group died within 30 days of randomization. Additionally, six patients in the tocilizumab group and five in the standard care group were intubated during that time.

The researchers concluded that there was no observed benefit with tocilizumab but noted that further study is needed to confirm the results and potential applications of tocilizumab at different disease stages.

In another study, Olivier Hermine, MD, PhD, of the Universitéde Paris and the Assistance Publique-Hôpitaux de Paris, and colleagues conducted a cohort-embedded, open-label Bayesian randomized control trial in patients with COVID-19 who had moderate or severe pneumonia that required supplemental oxygen but not ventilation or ICU admission. Patients were enrolled from nine hospitals in France.

In their study, Hermine and colleagues evaluated 60 patients assigned to tocilizumab plus usual care and 67 patients assigned to usual care only. The researchers said that usual care was at the discretion of physicians, and included antibiotic and antiviral agents, corticosteroids, vasopressor support and anticoagulants.

In the treatment group, patients received 8 mg/kg of tocilizumab intravenously and usual care on day 1, and then received another 400-mg dose of tocilizumab on day 3 if their required oxygen did not decrease by more than half. However, this decision was left to the treating physicians.

The researchers evaluated the proportion of patients who died or needed mechanical ventilation by day 4 — indicated by a score greater than five on the WHO 10-point Clinical Progression Scale (WHO-CPS) — and survival at day 14 without the need for noninvasive or mechanical ventilation.

Hermine and colleagues found that 12 patients in the tocilizumab group had a WHO-CPS score greater than five at day 4 compared with 19 patients who received usual care alone.

The researchers also found that in the tocilizumab group, 24% of patients required noninvasive ventilation, mechanical ventilation or died compared with 36% of the usual care group (median posterior HR = 0.58; 90% credible interval, 0.33-1.0).

The researchers did not identify a significant difference in mortality on day 28 between the groups.

Considerations for tocilizumab trials

In his editorial, Parr said all observational studies are subject to residual cofounding, and while the study by Leaf and colleagues can provide physicians with important insights in clinical management, “randomized trials will ultimately determine tocilizumab’s role in COVID-19.”

Although the study by Salvarani and colleagues had low rates of mortality, Parr said it excluded patients who were enrolled in the ICU, which likely contributed to the findings of a low mortality rate. In addition, he noted the findings were complicated because some patients in the comparator group also received tocilizumab.

The study by Hermine and colleagues, Parr noted, suggest that tocilizumab may improve patient outcomes at 14 days, but added that preliminary results from the COVACTA and EMPACTA trials make the significance of this finding unclear.

The studies, which are double-blind, placebo-controlled, randomized trials, also reported mixed results in their preliminary findings, Parr wrote.

He said that COVACTA did not meet its predefined efficacy thresholds and did not have a significant difference in mortality at 28 days, but it did find that patients treated with tocilizumab had reduced length of stay. The EMPACTA study, Parr wrote, demonstrated a reduction in mechanical ventilation or death by 28 days, but did not identify a significant difference in mortality at day 28.

Adarsh Bhimraj, MD, FIDSA, co-chair of the IDSA COVID-19 Treatment and Management Guidelines Expert Panel, told Healio Primary Care that the EMPACTA results suggest that there may be a slight benefit associated with tocilizumab in these patients, but the finding may be biased.

He said this is due to the composite outcome of both mechanical ventilation and deaths. Because there was not an observed difference in deaths at day 28 between the placebo and treatment groups, the primary outcome of both mechanical ventilation and death may have been driven primarily by differences in mechanical ventilation.

The decision to place a patient on mechanical ventilation is often seen as an objective outcome, but it is more subjective, Bhimraj said, because it can vary based on the individual physicians, the size of the hospital and which country it is located in.

He added that with composite endpoints, “it’s really hard to make any meaningful conclusions,” and that future trials should measure clinical endpoints separately.

“Even in double-blinded randomized controlled trials, it might be possible to ‘un-blind’ the study as patients receiving tocilizumab can have a decrease in [C-reactive protein] levels which can let the treating clinicians and investigators know who is receiving the placebo and who is receiving tocilizumab,” Bhimraj said. “This would not bias an objective outcome like mortality, but can certainly bias assessment of clinician-subjective outcomes like clinical improvement or duration of supplemental oxygen and ventilatory support requirement.”

Bhimraj also said studies have suggested that dexamethasone reduces the risk for mortality, and remdesivir has shown a slight benefit on hospitalization time in patients with COVID-19, so these treatments should be considered before tocilizumab, based on the findings observed at this point.

“If patients are absolutely not responding to that therapy, then you can try tocilizumab,” he said.

References:

Gupta A, et al. JAMA Intern Med. 2020;doi: 10.1001/jamainternmed.2020.6252.

Hermine O, et al. JAMA Intern Med. 2020;doi:10.1001/jamainternmed.2020.6820.

Parr JB. JAMA Intern Med. 2020;doi:10.1001/jamainternmed.2020.6557.

Salvarani C, et al. JAMA Intern Med. 2020;doi:10.1001/jamainternmed.2020.6615.