麻豆传媒

Tocilizumab (Actemra) didn't show clear evidence of efficacy against COVID-19 relatively early in the disease course in a slew of data from randomized trials and observational studies.

The monoclonal antibody against inflammatory interleukin 6 (IL-6), used primarily in rheumatoid arthritis, didn't reduce mortality or consistently improve other outcomes in hospitalized COVID-19 patients in the three randomized trials reported in the New England Journal of Medicine (NEJM) and JAMA Internal Medicine, despite more optimistic observational data.

STOP-COVID Study

The observational STOP-COVID study with 4,485 patients showed reduced mortality for patients who got tocilizumab within 2 days of ICU admission for COVID-19 (28.9% vs 40.6% at a median 27 days follow-up).

Tocilizumab's advantage persisted with a hazard ratio of 0.71 (95% CI 0.56-0.92) with inverse probability weighting to adjust for confounding, reported David E. Leaf, MD, MMSc, of Brigham and Women's Hospital in Boston, in

"However, there are potentially important differences in treatment groups at baseline (tocilizumab-treated patients were younger and had fewer comorbidities but were more likely to have hypoxemia and elevated levels of inflammatory markers)," cautioned Jonathan Parr, MD, MPH, of the University of North Carolina at Chapel Hill, in an accompanying

Randomized trials will ultimately determine tocilizumab's role in COVID-19, he wrote, and the totality of the new trial data don't support routine tocilizumab use in COVID-19 for now. "I plan to wait out the torrent of positive observational studies and reconsider tocilizumab's use in COVID-19 if, and only if, more compelling data from randomized trials emerges," Parr stated.

Tocilizumab use isn't recommend by the or outside of a clinical trial.

BACC Bay Tocilizumab Trial

In this 243-patient randomized, double-blind trial, tocilizumab didn't reduce intubation or death compared with placebo (10.6% vs 12.5% at day 28, HR 0.83, 95% CI 0.38-1.81).

The secondary endpoint of disease worsening likewise came out no better with tocilizumab (HR 1.11, 95% CI 0.59-2.10), reported John Stone, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues in .

Nor were there advantages in time to get off supplemental oxygen, duration of mechanical ventilation, ICU admission or death, or total hospital stay.

The trial enrolled patients (42% women; 43% white) with confirmed SARS-CoV-2, hyperinflammatory states (elevated C-reactive protein [CRP], ferritin, d-dimer, or lactate dehydrogenase), and at least two of the following signs: fever, pulmonary infiltrates, or supplemental oxygen to keep oxygen saturation above 92%.

Among them, 80% in a non-ICU hospital ward and on supplemental oxygen via nasal cannula, and a few (4%) were on high-flow oxygen. However, patients couldn't be on supplemental oxygen with a flow rate over 10 L/min.

Tocilizumab was given as a single dose at 8 mg/kg (not more than 800 mg total) along with standard care in all the trials. No new safety signals emerged.

RCT-TCZ-COVID-19 Trial

In this trial of 126 Italian patients hospitalized with COVID-19 pneumonia on nasal cannula oxygen, but not ICU-level care, tocilizumab didn't reduce the risk of clinical worsening within 14 days compared with standard care (28.3% vs 27.0%, RR 1.05, 95% CI 0.59-1.86).

That primary endpoint was defined by admission to the ICU and mechanical ventilation, death from any cause, or acute respiratory failure with a partial pressure of arterial oxygen to fraction of inspired oxygen (PaO₂/FIO₂) ratio of less than 150 mm Hg.

Nor were there differences in ICU admission before the randomized trial was stopped early for futility, reported Carlo Salvarani, MD, of Università degli Studi di Modena e Reggio Emilia, Italy, and colleagues in

The mortality rate was similarly low in both groups:

• 14 days: 1.7% vs 1.6% (RR 1.05, 95% CI 0.07-16.4)
• 30 days: 3.3% vs 1.6% (RR 2.10, 95% CI 0.20-22.6)

The trial included patients (38.9% women; mean age 60) with PaO₂/FIO₂ of 200 to 300 mm Hg and an "inflammatory phenotype" marked by fever in the prior 2 days or elevated CRP. Tocilizumab administration was started within 8 hours of randomization, a median 8 days from symptom onset.

The "surprisingly low" mortality was likely driven by exclusion of patients ineligible for ICU admission owing to comorbidities and clinical criteria that varied by site, Parr noted in the editorial. "The concept of ICU ineligibility will be unfamiliar to most US clinicians but was an unfortunate reality during Italy's pandemic response."

A major limitation was that 14 of the 60 usual care patients got tocilizumab due to clinical worsening, which "complicates interpretation of the results," Parr added.

CORIMUNO-19-TOCI-1 Trial

This open-label trial of 131 French patients with COVID-19 pneumonia requiring oxygen support outside the ICU likewise missed its primary clinical status endpoint but did show some secondary benefits to tocilizumab.

Twelve tocilizumab group patients versus 19 on usual care had scores higher than 5 on the WHO 10-point Clinical Progression Scale (denoting status worse than being on nasal cannula oxygen in the hospital) at day 4, which didn't meet the Bayesian statistical threshold for efficacy.

However, the drug reduced the likelihood of needing noninvasive or mechanical ventilation or death by day 14 (24% vs 36%), which did meet the predefined efficacy threshold, reported Olivier Hermine, MD, PhD, Université de Paris, and colleagues in.

Mechanical ventilation or death was a relative 42% less likely, but neither that composite outcome nor the relative 8% reduction in 28-day mortality was significant.

This trial had a population more representative of that in the U.S., making its findings easier to generalize, Parr noted. However, the significance of the secondary findings is "unclear in light of newly released preliminary results from the COVACTA and EMPACTA trials."

Topline findings released in press releases from those two double-blind, placebo-controlled showed:

• In , shorter hospital stays but failure to improve clinical status (the primary endpoint) or reduce mortality at day 28
• In 's largely racial and ethnic minority population, reduction of the composite of mechanical ventilation or death by day 28 but not mortality alone or any other endpoint

While remdesivir has been widely adopted without clear evidence of mortality benefit, whether reduced risk of mechanical ventilation in some patient populations "will depend on in-depth analysis of results from COVACTA, EMPACTA, and other studies nearing completion," particularly the RECOVERY trial, Parr suggested.

And there's still a chance that tocilizumab will prove itself in longer-term outcomes, he added. "It is possible that blunting the immune response with tocilizumab will reduce morbidity and mortality over the long haul. It is also possible that treatment-related adverse events and secondary infections will become more apparent over time, although these were rare in the studies described herein."

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