New trial of convalescent plasma for covid-19 falls flat, another setback for hyped treatment

Joshua Niforatos, MD, MTS
By
Research Section Editor

Is convalescent plasma the miracle treatment we were promised? The answer in the latest published clinical trial appears to be no. This is more worrisome news for a proposed treatment that has been bandied about and for which the US Food and Drug Administration granted emergency use authorization, despite the absence of compelling trial data to support its use (for more, see our prior coverage in March and August).

Released today, November 24, in The New England Journal of Medicine is a multicenter randomized, double-blind, placebo-controlled clinical (RCT) of 228 patients hospitalized with severe covid-19 who received either standard-of-care and convalescent plasma therapy or standard-of-care plus placebo. The primary outcome the researchers tracked was "clinical status" during follow-up at day 30.

The average age of participants was 62 years, and the majority were identified as male. Over one-fourth of patients were in intensive care units. Importantly, 93 percent of patients were on steroids, such as dexamethasone—meaning that they were already receiving the one treatment that has been shown to improve mortality rates in covid-19 patients with severe illness. 

Interestingly, 68.6 percent and 61.8 percent of patients given placebo and convalescent plasma, respectively, were discharged home in good condition, though that difference was not statistically significant. Unfortunately, by day 30 there were no significant differences noted between the convalescent plasma group and the placebo group with regard to clinical outcomes or mortality. Adverse events were similar in both groups. Previous retrospective studies have found that convalescent plasma can cause serious harms, despite the general talking point that "plasma is safe." But in a trial with just 228 patients, it is unlikely that many adverse events would occur.

The idea behind convalescent plasma makes sense: when fighting an infection, our bodies manufacture specific antibodies in bulk to combat an invading pathogen. After the infection, the body maintains a stock of "memory cells," meaning that in the event of a future infection by the same virus, bacteria, or other infectious disease, our response can be both rapid and specific. Some antiviral antibodies circulate in the blood, almost like molecular surveillance drones. If an infection re-appears those antibodies spring into action. 

By mid-August it was announced that over 60,000 people had already received convalescent plasma therapy for covid-19, despite any high quality evidence of its ability to improve morbidity or mortality. Since that time, likely tens of thousands of additional patients have been given this medical therapy, largely owing to the FDA's emergency use authorization. This new study adds to a growing list of randomized trials that have failed to show a benefit for this treatment. So far, only retrospective studies have been "positive." When retrospective studies and randomized trials conflict, the trials should be seen as more definitive. 

More trials are ongoing. While that is good, it is important to remember that if enough trials are conducted, one or two may find a marginal benefit, just as a result of statistical chance. Any positive findings would have to be weighed against the totality of the other existing evidence. At this time, we continue to believe that most patients should not be receiving convalescent plasma therapy outside of formal clinical trials.


Moderna announces interim covid-19 vaccine data – reports 94.5% effectiveness

Joshua Niforatos, MD, MTS
By
Research Section Editor

As we mentioned last week with our briefing on Pfizer's mRNA covid-19 vaccine, the short-term future of the country may be riding on an effective vaccine. A glimmer of hope was revealed last week as Pfizer and BioNTech released interim data from their phase 3 randomized clinical trial of an mRNA vaccine candidate that was reported to be "90% effective". Enter the 94.5% effective Moderna vaccine. 

In breaking news today, the Cambridge, Massachusetts-based biotechnology company Moderna, Inc. (Nasdaq: MRNA) announced interim results of its phase 3 randomized clinical trial (RCT) of an mRNA vaccine candidate. In this trial, 30,000 individuals aged 18 years of age and older were enrolled and randomized to receive either the mRNA vaccine or a placebo injection on day 1 and day 29. 

The primary outcome of the study was the number of participants with a first occurence of syndromic covid-19 occurring 14 days after the day 29 second dose of the mRNA vaccine, as well as incidence of side effects. 

The data provided by Moderna today were limited. So far, we know that 95 cases of symptomatic covid-19 were detected, 90 of which were in the placebo group (i.e. those who did not receive the mRNA vaccine). There were a total of 11 severe cases, all of which occurred in the placebo group and zero in the mRNA vaccine group. The side effect profile was considered tolerable with only common vaccine side effects, such as pain at the injection site, fatigue, and aching muscles and joints noted. 

How does this compare to last week's news that Pfizer/BioNTech covid-19 vaccine was "90% effective"? To summarize, in the Pfizer/BioNTech's vaccine results made public last week, 90% of participants who received the candidate vaccine did not develop symptomatic covid-19--though it remains possible  that people who received the vaccine could still have contracted the SARS-CoV-2 virus but were asymptomatic carriers and vectors (i.e. could still spread) of the disease. We still don't know. 

Key differences between the Moderna and Pfizer/BioNTech vaccine are described in the infographic accompanying this article. One advantage of the Moderna vaccine is that it can be stored in warmer conditions, including normal refrigeration up to 30 days. Another advantage includes increased effectiveness in preventing covid-19 symptoms (94.5% vs 90%). But both vaccine trials had similarities that are important to highlight, including large and diverse patient populations and the fact that overall no major safety concerns emerged. What we still do not know regarding the Pfizer vaccine is the exact breakdown of how many covid-19 cases occurred in the placebo versus the vaccine group, and how many cases of severe covid-19 occurred in the vaccine group. This is in contrast to information provided by Moderna that shared slightly more granular data. 

What does this news mean? In one respect, little has changed. We still do not know whether these vaccines prevent infection and spread, and for how long protection lasts. (The vaccine uses mRNA vaccine technology that has only recently become feasible and has never been approved for similar purposes). Does the vaccine protect the elderly? Does it protect those with immune system dysfunction? Time will tell. On the other hand, we now have a second vaccine that targets the surface proteins of SARS-CoV-2 that shows signs of effectiveness. This ratifies the scientific community's general approach to developing a vaccine faster than at any time in human history.

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Another hope dashed - Tocilizumab not as promising as hoped in a new trial

Earlier this week we covered three JAMA Internal Medicine papers assessing drug called tocilizumab, a monoclonal antibody that targets interleukin-6 receptors, thought to contribute to the human body's counterproductive immune response to SARS-CoV-2, the virus that causes covid-19. The studies from earlier this week were disappointing overall but left us with a glimmer of hope that the medication might still benefit a subset of patients.

The idea is that this medication reduces the inflammatory response seen in critically ill patients with covid-19. Released today in New England Journal of Medicine is an industry funded study looking at this drug's efficacy. Sadly these results are also not promising. Researchers at Massachusetts General Hospital studied whether drug administration affected the need for mechanical ventilation or death, prior to intubation. This well performed double-blind placebo-controlled study required patients to have confirmed SARS-CoV-2 and at least two of the following clinical features: fever, abnormal lung findings on radiological imaging (such as chest x-rays of CT scan), or the need for supplemental oxygen.

A total of 243 patients (58 percent of whom were men) were enrolled who had a median age of 59.8 years. Tocilizumab was found to have a hazard ratio of 0.83 for intubation or death, but the ratio crossed the 1.0 threshold (less than 1.0 would indicate fewer deaths, more than 1.0 would indicated more deaths), meaning that it cannot be said to be a statistically meaningful result (the authors are 95 percent certain that the "true" ratio is somewhere between 0.38 and 1.81). At two weeks, 18 percent of the patients who received the monoclonal antibody drug had disease worsening compared to 15 percent among those who received placebo. The discontinuation of supplemental oxygen was very similar in both groups as well (5.0 days vs 4.9 days).

Of note, a reasonable portion of the patient group studied was Hispanic or Latino (45 percent) which does tend to reflect previous studies looking at patient demographics hospitalized with severe or critical cases of covid-19.

Unfortunately the use of the monoclonal antibody, tocilizumab was not found to prevent death or intubation in patients with covid-19. Given the very large confidence intervals it was hard for the authors to draw a conclusion as to whether this medication is harmful or helpful to patients with respect to a number of different clinical outcomes.


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