Medicine Matters rheumatology

The rationale for doing our trial was that it is very clear, or it seemed clear, that there is an inflammatory state which may actually super lean after the infectious period. And that is actually this hyper inflammatory state characterized by cytokines that leads to the respiratory and multi organ decline of patients with COVID-19. And it's this hyper inflammation that actually leads to the need for intubation, mechanical ventilation, and sometimes leads to patient's death. So we hope to be able to interfere with this by giving IL-6 receptor blockade.

IL-6 has been postulated to be a central cytokine in this hyper inflammatory state. And we hope that by interfering with that, we might disrupt the cascade and lead to better outcomes. This was a randomized double blind placebo controlled trial of standard care plus either tocilizumab given via one intravenous dose or placebo, which was normal saline. The primary endpoint in the trial was time to intubation or for patients who died before they could be intubated, time to death.

There were also a couple of other very important secondary outcomes which were clinical worsening, as measured on an ordinal scale and time to discontinuation of supplemental oxygen. There were a variety of other tertiary and exploratory endpoints. In summary, we found that with regard to the primary endpoint, the two major secondary endpoints, and all of the tertiary and exploratory endpoints, we found no evidence, unfortunately, that tocilizumab led to better outcomes in the patients who were in the tocilizumab group, as opposed to the placebo group.

Patients treated with tocilizumab were just as likely to be intubated, and/or to die. They were just as likely to worsen. They had just as long a time required on supplemental oxygen, and the other outcomes. This was true despite multivariate analysis that we did, which corrected for age, diabetes status, baseline, serum IL-6 concentration, and a variety of other variables that are thought to be important in determining patients’ outcomes.

Well, I think it's a pretty classic case of the observational studies being biased by placebo effect and some of the other biases that some studies that are not randomized double blind placebo controlled fall prey to. The majority of patients with COVID get better. 12% of the patients in our trial nevertheless, died. But the majority of patients get better. And if one has given tocilizumab on an open label basis and the patient improves, then it's a natural conclusion to jump to that it must have been because of the tocilizumab that patients received.

But in fact, we never know that that is true for certain, unless we do the gold standard clinical investigation. And that's the randomized double blind placebo controlled trial. In fact, the majority, the great bulk of data from the few randomized controlled trials that have been done with tocilizumab, or some other mode of IL-6 receptor blockade, really support by and large the findings in our trial. They are basically negative trials, in contrast to many of the open label studies done so far.

That's a good question. Is it the end of the road for IL-6 receptor blockade in COVID-19? The confidence intervals in the outcomes in our trial were very wide. So the implication of that is we cannot be 100% certain that there is not some subset of patients, maybe with more severe disease than the patients we enrolled, who might benefit from IL-6 receptor blockade. It is equally possible that there might be harm that occurs to some patients through tocilizumab, although we didn't see any indication of that in our trial.

So we cannot be 100% certain that IL-6 receptor blockade is not effective across the board considering all patients with COVID-19 infections who are hospitalized. I do think that definitive answers are likely to come from trials that are ongoing now that are substantially larger than ours. We enrolled 243 patients at the height of the pandemic here in Boston, or the first surge anyway, which was I think very adequately powered trial.

But there is at least one other trial that's going to include up to 2000 patients. And if there is a small effect that we did not detect in our trial, then it's possible that larger trial will find it. And I think that will be the definitive answer. So far, the results for IL-6 receptor blockade are really rather discouraging on the whole.