What science has learned works and what doesn’t in COVID-19 treatments.
By Karen Weintraub, USA TODAY
A year after the first COVID-19 patient was treated in the United States, a number of medications and approaches have been studied and found effective, while others have shown little benefit.
There are 394 treatments and 241 antivirals still being developed against COVID-19, and drugs already approved by the U.S. Food and Drug Administration or readily available over-the-counter remedies are being studied to see if they make a difference.
Dr. R. Scott Wright, a cardiologist and clinical trialist at the Mayo Clinic, said researchers are eager to find treatments that work. But that takes time, money, effort and patients willing to participate in trials.
"There is no conspiracy to keep therapies out of the public," he said. "Doctors and nurses are dying at the same rate as the non-medical community. We don't want one more person to die."
Here's a list of some of the best known tools studied over the last year:
Treatments with solid scientific support
Dexamethasone, an inexpensive, long-used steroid, was shown by a large British trial to be effective in treating the most serious cases of COVID-19: hospitalized patients on supplemental oxygen or a ventilator. Some data suggest steroids may be harmful if given too early, before patients are hospitalized and need supplemental oxygen.
"One third of people on vents, their lives are saved with a drug that costs $1 a day," said Dr. David Fajgenbaum, an assistant professor of medicine at the Perelman School of Medicine at the University of Pennsylvania.
Even with that, more research would be helpful Fajgenbaum said. The dose that's given "was the first dose anyone tried," he said. "Maybe double is more effective, or half."
Proning, or turning someone on their stomach, can help improve lung function, studies on patients in respiratory distress have long shown; research on its use in COVID-19 have been supportive, as well. This has become an established practice for COVID-19 in intensive care units around the world.
Remdesivir, an antiviral, is authorized for use in COVID-19 patients by the U.S. Food and Drug Administration, though the World Health Organization determined it did not prevent death or other bad outcomes.
As an antiviral, remdesivir is likely to have its greatest effect in patients who are early in their disease course, before they are hospitalized. But the drug has to be given by infusion, rather than a shot or a pill, making it impractical to deliver to patients who aren't yet hospitalized.
Baricitinib, an immunosuppressant, is currently authorized for use in COVID-19 in the U.S. In one recent trial, remdesivir plus baricitinib was found to be superior to remdesivir alone in reducing recovery time and accelerating improvement in hospitalized COVID-19 patients, particularly those receiving high-flow oxygen or noninvasive ventilation.
Monoclonal antibodies, several of which are FDA-authorized, provide at-risk patients with a concentrated dose of antibodies to help them fight disease. Similar in theory to convalescent plasma, drug companies develop monoclonals by studying antibodies that helped other patients recover. But monoclonals are considered more consistent and reliable than blood products from recovered patients, which can vary in their concentration and effectiveness.
Former President Donald Trump was so impressed with the benefit he got from monoclonal antibodies when he had COVID-19 that he got the government to purchase millions of doses to be delivered at no cost to high-risk patients.
Unfortunately, many of these doses are still sitting on pharmacy shelves, because they are tricky to deliver. They must be given early in the course of disease, before a patient is sick enough to require hospitalization – and before many people seek or are offered medical care. They also are delivered by infusion, a process that takes up to about an hour. Patients are at their most contagious when these drugs will be most effective, and many hospitals and medical facilities lack staff and physical spaces where they can deliver the drugs safely.
A federal research trial of an antibody from Eli Lilly Company in hospitalized patients failed, supports the idea that timing matters in COVID-19 treatment.
Because monoclonal antibodies are very targeted, they also are at risk for becoming ineffective against variants of the virus. For COVID-19, monoclonal antibodies – including FDA-authorized ones from Lilly and Regeneron Pharmaceuticals – are given as "cocktails" of two drugs to ensure they remain effective.
Tocilizumab, a drug that tamps down a certain kind of inflammation, reduces the risk of death for patients seriously ill with COVID-19 whose bodies are mounting an immune attack against them, two recent studies out of Europe and the U.K. showed.
The Infectious Disease Society of America updated its treatment guidelines in February to conditionally support the use of tocilizumab in addition to steroids for hospitalized adults with severe COVID-19.
Also, the National Institutes of Health recently added tocilizumab to its treatment guidelines in combination with dexamethasone for hospitalized patients who need substantial oxygen support.
Anti-coagulants, intended to thin blood and prevent blood clots, make sense as a treatment in COVID-19, with early indications they will be effective. In one recent study, patients given blood thinners in the first two days of their treatment in intensive care had similar survival rates as those who did not receive the treatment.
But three trials being conducted around the world, supported in part by the U.S. government, suggest that full dose blood thinners given to moderately ill hospitalized patients reduced the need for ventilation and other "vital organ support." Another study showed anti-coagulants reduced a patient's chance of dying within 30 days.
Treatments with potential but limited evidence
ECMO, or extracorporeal membrane oxygenation, takes over lung function and early research has shown it to be a life-saver for the sickest patients, according to a recent Harvard study.
One study of the drug fluvoxamine, used to treat obsessive-compulsive disorder, showed promise, but was too small to determine effectiveness against the virus.
Cyclosporine, used to treat rheumatoid arthritis and psoriasis and to prevent rejection in organ transplant patients, has antiviral effects and is able to block proteins that can trigger dangerous immune system overreactions in seriously ill COVID-19 patients, said Dr. Carl June, an expert in immunotherapy at the University of Pennsylvania in Philadelphia.
Although promising, no well-designed trials have been performed to assess its effectiveness and there are no plans for a major national trial of the drug, which is long off-patent. (It's difficult to find money to run clinical trials on drugs no longer protected by patent.)
June is leading a trial in collaboration with researchers at Baylor University in Houston to test the drug in patients on oxygen who also receive dexamethasone.
"It could be very useful, especially in low- and middle-income countries where they're never going to be able to afford the expensive antibody therapies," he said.
(Cyclosporine) could be very useful, especially in low- and middle-income countries where they’re never going to be able to afford the expensive antibody therapies.
As with other COVID-19 drugs, the dose and timing of cyclosporine is important. Give it too early and it could tamp down the immune response in people who still need to fight the virus.
At Brigham and Women's Hospital in Boston, researcher JoAnn Manson is studying whether vitamin D can help protect against COVID-19. She speculated in a November paper that vitamin D deficiencies, which are particularly common among people of color, may contribute to their worse outcomes with the disease. Clinical trials of vitamin D have so far shown differing results, with a single high dose of the vitamin shown to be ineffective for hospitalized patients with moderate to severe disease.
Famotidine, commonly known as Pepcid, decreases stomach acid. Medical records from China showed that early patients with COVID-19 fared better if they were taking famotidine.
Early research into the drug as a treatment against severe disease has been mostly negative and inconclusive, according to the Infectious Disease Society of America's practice guidelines. They recommend not using famotidine outside of a clinical trial.
Another trial is looking at NAC or N-acetylcysteine, used to treat acetaminophen overdoses and emphysema and theoretically could slow a viruses' ability to replicate and prevent blood clots in COVID-19 patients.
A community hospital outside Boston is running a clinical trial, based on early data suggesting the drug might be helpful. With only a small outside grant, principal investigator Dr. Melisa Lai-Becker, an emergency medicine specialist at Cambridge Health Alliance, is struggling to figure out how to structure the trial so it can compare the drug to a placebo.
She's intrigued by the possibilities of NAC, she said, because it's a very safe medication, used since the 1970s, doesn't require a prescription and costs just 7 cents a pill. "The payoff could be tremendous," she said – if it's proven to work.
Intravenous immunoglobulin, a rich source of antibodies to help a sick person fight off the virus, has been the subject of a few small trials suggesting a possible benefit. One small study out of Iran found that hospitalized patients who received IVIg were significantly less likely to die than those who didn't get the antibodies.
An outpatient study of the gout drug colchicine suggested it offered some benefit early in COVID-19 infections, but the effect was not statistically significant and the trial still hasn't been published in a peer reviewed medical journal. Another found some support for using colchicine among hospitalized COVID-19 patients.
Meanwhile, a British trial of the drug in hospitalized patients was discontinued this month after an independent review board found "no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any pre-specified subgroup." The same trial is continuing to study whether COVID-19 patients can benefit from aspirin, baricitinib, Regeneron’s antibody cocktail or the multiple sclerosis drug dimethyl fumarate.
Ivermectin, used to treat parasitic worms, has been floated as a potential COVID-19 treatment, but research does not support its use. A study published March 4 found it did not shorten the time someone had symptoms of COVID-19. The National Institutes of Health says it can neither recommend nor suggest against using ivermectin to prevent or treat COVID-19, while the FDA strongly recommends against using the drug, particularly in the form designed to be used in animals.
But the public has been slow to get the message. According to data from prescription savings service, SingleCare, there was a 1,126% increase in ivermectin prescriptions in January 2021 compared to a year earlier, and a 464% increase in February 2021 compared to February 2020.
Interferons, immune proteins that modulate the response of the immune system to viruses, are crucial for mounting an immune response. The inhaled version of interferons was found to be quite effective for hospitalized patients.
A study out late last year found some people with life-threatening COVID-19 had genetic quirks that left them interferon-deficient. But for those with normal gene function, adding interferons didn't seem to help. A large study run by the World Health Organization found that interferons, hydroxychloroquine and lopinavir-ritonavir all "had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay."
Drugs shown to be ineffective
The combination of lopinavir-ritonavir, two drugs used to fight HIV, don't help hospitalized COVID-19 patients. This was among the earliest treatments tried against COVID-19, and hopes were initially high it would prevent infected people from getting sick, but trials didn't support the effort.
Hydroxychloroquine, the anti-malarial drug touted by Trump, doesn't help and might hurt COVID-19 patients. The FDA has recommended against its use in non-hospitalized COVID-19 patients. Although its popularity peaked around the time Trump was touting it, its use remained well above pre-pandemic levels through the end of 2020.
Insulin treatment did not appear to benefit COVID-19 patients with type 2 diabetes, according to a study early in the outbreak in China, though aggressive glucose control seemed to help.
High dose zinc and vitamin C are often considered to be immune boosters, but a small trial using these supplements in non-hospitalized COVID-19 patients was ended early because it failed to show any benefits. Patients received either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both or neither. Sales of vitamin C supplement skyrocketed 76% to about $209 million during the first half of 2020 compared to a year earlier, according to Nielsen research. Zinc use rose roughly in parallel with peaks of infections in 2020, climbing four-fold by the end of the year.
Convalescent plasma, although authorized for use by the FDA, there's very little evidence these blood products from recovered patients are consistently effective. The National Institutes of Health recently discontinued a study of convalescent plasma in emergency rooms, saying it wasn't preventing patients from getting sicker. Another recent study of 1,000 COVID-19 patients found no evidence that plasma shortened their hospital stay, avoided the need for mechanical ventilation or improved patient outcomes.
Contact Karen Weintraub at kweintraub@usatoday.