Conquering COVID Part 2.1:
“RECOVERY from COVID-19 looks more promising because of a drug approved in 1958?!” (aka New UK trial teaches us lessons on being selfless, modest, & cheap just like when treating a disease with Citrus Fruits?!)
June 24, 2020
by Mark A. Moyad, MD, MPH
“I am concerned, of course, but I am also incredibly optimistic.”
Hi my friends! Yes, I missed you too! I decided to take several days off from this column for many reasons, including the fact that I wanted to remind my spouse we are definitely married to each other, because I am definitely not married to my computer. Another reason I wanted to wait was due to the fact that I knew the results of several clinical trials could be coming out in later June, and then I would comment on them. Well, we certainly got some results from several studies including one amazing and ongoing trial known as “
RECOVERY” (
Randomized
Evaluation of
COVid-19 th
ERap
Y”). In March of this year, the RECOVERY trial was initiated to test a series of treatment options for COVID-19 and now over 11,500 participants have been enrolled from over 175 National Health Service (NHS) hospitals in the United Kingdom (UK)! How brilliant was this! The researchers wasted little-to-no time during the pandemic and designed and implemented a multi-arm and multi-site study. The RECOVERY trial is testing the following medications (we have covered most of these in past columns, so if you have been reading this series of COVID articles you get an A+, and if you have not been reading the articles then you have hurt my feelings):
- Azithromycin (popular antibiotic-known by some as a “Z-Pak”)
- Convalescent plasma (collected from recovered patients and contains specific antibodies)
- Dexamethasone (type of steroid use for a variety of conditions to reduce inflammation)
- Hydroxychloroquine (NO LONGER TESTING, used to treat malaria, lupus, rheumatoid arthritis)
- Lopinavir/ritonavir (also known as “Kaletra”, commonly used drug for HIV)
- Tocilizumab (also known as “Actemra,” a targeted injectable immune-suppressive drug)
When you look at the range of individual drugs being tested for patients with COVID-19 then you can see the fabulous diversity of products, which is why it is also a brilliant trial. I love that word “brilliant,” and if you have ever been to the UK, it is a word generally utilized in a very positive sense and also exemplifies verve. For example, “Dr. Moyad is brilliant, and his column is brilliant, and his research results or reports are brilliant.“
Anyhow, researchers wanted to do a trial they could immediately learn from…whatever the results. On June 5, 2020 the research team sent out a note that read “
no clinical benefit from use of hydroxychloroquine in hospitalized patients with COVID-19.” A total of 1,542 patients were randomized to hydroxychloroquine versus 3,132 patients to usual care alone. No significant difference was found for the primary endpoint of 28-day mortality and, in fact, it was 25.7% with the drug and 23.5% with usual care (hazard ratio 1.11; 95% CI: 0.98-1.26; p=0.10). This observation suggests there could have been some harm with hydroxychloroquine, or simply that it did not do anything beyond usual care. When researchers looked at other potential benefits in hospitalized patients, there were none to be found (for example the time spent in the hospital). So the independent committee for the RECOVERY trial suggested to stop this arm of the study and it was stopped.
Now, let us return to the RECOVERY trial, because the latest report from the RECOVERY trial delivered some wonderful news! They arguably found the first drug to improve survival in COVID-19, and it is low cost and immediately available, and it is known as DEXAMETHASONE! Wow! We can now review the, yet to be published in a medical journal, clinical results. A total of 2,104 patients were randomized to receive 6 mg of dexamethasone once per day via IV injection, or by mouth, once a day for 10 days compared to 4,321 patients receiving usual care. The 28-day mortality was 41% (the highest) among patients requiring ventilation, and mortality was 25% in those requiring oxygen, and it was lowest, or 13%, among those not requiring any respiratory assistance. Thus, before discussing the drug results, you can see that when needing mechanical ventilation, there is the highest risk of dying from COVID-19 in the hospital, and an intermediate risk of dying when needing supplemental oxygen, and the lowest risk of dying when being hospitalized, but not needing ventilation or oxygen. This, of course, makes sense - with greater severity of COVID-19 or greater breathing issues, then the greater the risk of mortality. Although, in a later edition of this column we will also discuss how COVID-19 can also impact other parts of the body, including the cardiovascular and gastrointestinal system.
Now, the dexamethasone part of the RECOVERY study was stopped, and below is a 5-point summary of the generally good results overall (but of course results from a study will never be perfect results until no one dies of COVID-19):
- DEXAMETHASONE reduced deaths in HOSPITALIZED COVID-19 patients with SEVERE DISEASE-patients receiving VENTILATION by approximately ONE-THIRD=-35%, (RR=0.65, 95% CI 0.48-0.88, P=0.0003) vs. usual care.
- DEXAMETHASONE reduced deaths by approximately ONE-FIFTH=-20%, (RR=0.80, 95% CI 0.67-0.96, p=0.0021) among patients requiring OXYGEN alone vs. usual care.
- Investigators estimated that GIVING DEXAMETHASONE TO 8 VENTILATED patients or 25 REQUIRING SUPPLEMENTAL OXYGEN would prevent 1 DEATH.
- DEXAMETHASONE did NOT show a benefit for patients who did not require respiratory assistance or support (NOT RECEIVING/REQUIRING OXYGEN) in the hospital. (RR=1.22, 95% CI=0.86-1.75).
- DEXAMETHASONE reduced the 28-day mortality OVERALL by 17% (0.83; 0.74-0.92; p=0.0007) with a very significant trend for those needing to be placed on VENTILATION (p for trend <0.001).
So, we have learned a lot from this RECOVERY trial! Dexamethasone is a low cost old steroid drug that appears to potentially reduce the ugly inflammatory reaction that occurs with more severe COVID-19 disease, and works well enough to save lives! However, in less severe HOSPITALIZED patients with COVID-19 where the inflammatory response is not as severe, or perhaps, not the primary issue, then this drug was not effective. It appears that earlier in the course of the disease process with COVID-19, you need your immune system to help you fight the virus, but as the disease becomes more severe, than an exaggerated immune response or too much boosting can be harmful. Interestingly, we discussed this possibility months ago in past columns so, despite what some Monday morning quarterbacks (or Tuesday morning quarterbacks if you only watch Monday Night Football) are saying about some researchers or health care professionals not understanding the disease process, it does appear that they really did understand it early on, in theory, since this U.K. trial would have otherwise never utilized dexamethasone or a drug to suppress the immune system.
Thus, this trial opens the door to using a different drug with a different mechanism of action earlier in the course of the disease process. ALTHOUGH, KEEP IN MIND THAT THE RECOVERY TRIAL DID NOT TEST PATIENTS OUTSIDE OF THE HOSPITAL, which still leaves doors open to this treatment in other situations, or testing a combination treatment. For example, the other known or potentially effective COVID-19 drug “remdesivir” in combination with this drug should be an interesting result.
Yet, this is an AMAZING DAY LADIES and GENTLEMEN! Why? I am glad I asked myself this question. I have to shake my head as I am writing this column because the first two drugs ever proven to work against the virus that causes COVID-19 are:
- REMDESIVIR, which was a drug that previously had no “established safety or efficacy for the treatment of any condition” until COVID-19. In fact, it had been tested for several other conditions in the past, including Ebola virus and some other viral diseases, and it was not effective enough. Regardless, here is a drug not being used for anything and it comes off the shelf (basically) to show some potential efficacy against COVID-19. The FDA has approved it for use “at any time after onset of symptoms in hospitalized patients.” The company that makes this drug is now testing an inhalable version, which could be used at home. The real interesting point here is that this drug appeared to work better for those hospitalized, but not needing mechanical ventilation. However, dexamethasone was working better in those patients needing mechanical ventilation. This again suggests, at the earliest stages of COVID-19, the virus itself causes someone to become sick, and at later stages the over stimulation of the immune system contributes to the illness and increases the risk of dying of the disease. Thus, an anti-viral drug could have some good efficacy if used early in the disease process, or when symptoms are just beginning. THIS IS EXCITING because researchers are learning quickly how to precisely target this disease.
- DEXAMETHASONE results were actually outstanding, in my not so humble opinion, because if you needed a drug to be helpful in the first few months of the pandemic, it would be ideal to find one that worked in the most sick patients, which is also very cheap, and also available almost anywhere in the world right now, and that is exactly what was found with the drug DEXAMETHASONE! In fact, DEXAMETHASONE WAS FIRST APPROVED BY THE FDA ON OCTOBER 30, 1958! It is also of interest to me that this was a United Kingdom multi-arm trial, and arguably the first ever officially conducted and published multi-arm or multi-group trial in the world was completed in the 1700s by another U.K. doctor whose name was James Lind. Ever heard of him? He was the one that tested sailors with a variety of products that were suffering from a terribly debilitating disease that also caused numerous deaths. It appeared in his clinical trial that the group of sailors allocated or consuming CITRUS FRUITS - actually two oranges and one lemon daily (Mine I. J R Soc Med 2012; 105: 503-508) were recovering from, and even being CURED of this terrible disease. The secret ingredient in the citrus fruits was later determined to be VITAMIN C, and the disease is known as “SCURVY!" This is another history lesson to, not only think about what you can create to cure a disease, but also what you can currently utilize to cure a disease. Of course, we always need to look forward and determine how we can create better, and more effective treatments, and this kind of thinking can dramatically change lives, as witnessed with HIV and HEPATITIS C drugs, for example. Still, we have 1,000s and 1,000s of drugs sitting on shelves, or that have been approved decades ago that have the potential to be repurposed for other diseases, and dexamethasone is a classic example of why good researchers should always look forward, but also backward to potentially and eventually move forward. There is a somewhat similar aphorism in philosophy and history about learning from the past in order to improve the present and future, and this also applies to medical history. The RECOVERY trial researchers and participants are selfless heroes! Egos were placed on a shelf to research an old generic drug that was/is currently sitting on many pharmacy shelves! The results of this study would IMMEDIATELY save countless lives! Today, many people want press releases, ego boosts, fortune from a patented product, TV time… but members of the RECOVERY trial just wanted to do what Dr. Lind wanted to do back in the 1700s…cure a terrible disease! It is why this is one of the best medical research stories I have come across in some time, and I was compelled to write about it because it is symbolic of the beauty all around us when you decide to go looking for it!
Thank you for reading my latest installment and I wish you and your family the best of health.
I am concerned, of course, but I am also incredibly optimistic! I look forward to modern day science and you of course, kicking COVID-19 and cancer in the gluteus maximus!
All of my best always,
Mark A. Moyad MD, MPH
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