LONDON – After a number of equivocal small studies, the U.K. Recovery trial has applied its heft to turn in statistically significant evidence that the rheumatoid arthritis treatment Roactemra (tocilizumab) reduces mortality in hospitalized COVID-19 patients.

In the 4,000-patient study, in which half received standard of care and half standard of care plus a single one-hour infusion of Roactemra, treatment with the interleukin-6 inhibitor significantly reduced deaths. In total, 596 (29%) of the patients in the Roactemra group died within 28 days, compared to 694 (33%) patients in the standard-of-care group (p=0·007).

That was an absolute difference of 4% over and above the benefit of treating patients with dexamethasone, now part of the standard of care, and which 82% of all patients in the trial were receiving. That means for every 25 patients treated with Roactemra, one additional life would be saved; of all COVID-19 patients admitted to hospital in the U.K. today, 36 will survive who may not have done otherwise.

Roactemra also reduced the length of hospital stay and the need for mechanical ventilation. Among patients not on invasive mechanical ventilation when they entered the trial, Roche Holding AG’s drug significantly reduced the chance of progressing to invasive mechanical ventilation, from 38% to 33% (p=0·0005).

The benefits were seen in all patient subgroups, including those requiring oxygen via a simple face mask, through to those on mechanical ventilators in an intensive care unit.

“Everybody pretty much now is treated with dexamethasone, so the question is, does tocilizumab have an added effect?” said Martin Landray, professor of medicine and epidemiology at Oxford University, who is joint chief investigator. “There are quite large benefits that are consistent in every group of patients; young and old, men and women, of different ethnicities and across different ventilation [methods]. All benefits are in addition to dexamethasone,” he said.

The combined effect of giving Roactemra and dexamethasone to COVID-19 patients with hypoxia and significant inflammation is to reduce mortality by about one-third for patients requiring simple oxygen, and by nearly one-half for those requiring invasive mechanical ventilation.

As Landray put it, “this is a big old number. We wouldn’t know this without the Recovery trial,” he said. “This will change practice, not only here in the U.K., but globally.”

Making an analogy to treating heart attacks, where a number of drugs are used that have small effects individually, but a big impact when combined, Landray said there will be more to discover. “There is high mortality and lot of patients, so small [improvements] matter,” he said.

Previous results inconclusive

The key reason why it was possible to show dexamethasone and Roactemra are effective – and to test and reject four other drugs in the 11 months since Recovery got off the ground – is the ability to run a single national trial.

On Feb. 11, patient number 36,000 was recruited to Recovery. “It’s not just that we have a lot of cases, but we have the contribution of the whole of the National Health Service,” said Landray. “That contribution is incredibly powerful. Patients are treated better because of clinical trials and that is how we change the face of COVID.”

The results also put to rest uncertainty over the use of IL-6 inhibitors in treating COVID-19. Roche has reported middling to inconclusive results for Roactemra, with the monoclonal antibody failing to meet the primary endpoint in the Covacta study that reported in July 2020.

The drug had a slight effect in reducing the number of hospitalized patients requiring mechanical ventilation over 28 days, but failed to meet key secondary endpoints, including reducing time to hospital discharge and time to clinical failure, in another study published in September 2020.

Given previous trials of Roactemra had shown mixed results, it was unclear which patients might benefit, said Peter Horby, professor of Emerging Infectious Disease at Oxford University and the other lead investigator on Recovery. “We now know that the benefits of tocilizumab extend to all COVID patients with low oxygen levels and significant inflammation,” he said.

Included in the report of the Recovery data posted on the preprint server Biorxiv, is a meta-analysis Horby and Landray completed of all other previous studies of Roactemra in COVID-19. “Until the results today, [trials] have been inconclusive. When you put Recovery on top, you have four times the amount of deaths and substantially more people – it becomes clear cut,” Horby said.

In June 2020, the Recovery trial reported the inexpensive and widely available drug dexamethasone reduced the risk of death by one-third for patients on an invasive mechanical ventilator, and by one-sixth for those requiring oxygen. Horby said recent research indicates 12,000 lives in the U.K. and 650,000 worldwide have been saved as a result.

The Recovery trial previously announced results showing hydroxychloroquine, the HIV combination treatment lopinavir-ritonavir, azithromycin and convalescent plasma have no benefits for patients hospitalized with COVID-19.

The trial is continuing to investigate the use of aspirin as an anti-coagulant, the anti-inflammatory drug colchicine, and Regeneron Inc.’s antiviral antibody cocktail, REGN-CoV2.

And just last week Eli Lilly and Co.’s JAK inhibitor, Olumiant (baricitinib), was added to the study. That arm already has recruited 800 patients, Horby said.