COVID-19 Treatments: What's In, What's Out

Countless therapies have been tried for COVID-19. Not all have failed as spectacularly as hydroxychloroquine, so it can be difficult to keep track of what's been proven to work, and what has not.

Below is a live list of currently authorized and/or validated therapies -- noting the stage of disease for which they work best -- as well as some others that didn't pan out or are still under evaluation.

MedPage Today will continue to update this list as new information becomes available.

Treatments in Use

Remdesivir

Remdesivir (Veklury), an antiviral, is currently the only FDA-approved therapy for COVID-19. It was approved in October 2020 for hospitalized COVID-19 patients ages 12 and up who weigh at least 88 lbs. Its original emergency use authorization (EUA) has been revised to also allow for treatment of hospitalized pediatric patients under 12 who weigh at least 7.7 lbs.

FDA also issued an EUA for the combination of remdesivir plus the oral JAK inhibitor baricitinib (Olumiant) in hospitalized patients with severe COVID-19. (See baricitinib section below.)

NIH guidelines recommend the use of remdesivir in hospitalized patients who require supplemental oxygen, either on its own, or in combination with dexamethasone. For those requiring high-flow or noninvasive ventilation, NIH recommends remdesivir only in combination with dexamethasone.

The NIH originally recommended remdesivir for use in mechanically ventilated patients, but limited its scope of use in December 2020, due to a "lack of data showing benefit at this advanced stage of the disease."

Dexamethasone

Dexamethasone, a corticosteroid with potent anti-inflammatory effects, is recommended for use in many categories of patients hospitalized with COVID-19, but not for those with mild-to-moderate disease who aren't in the hospital.

While it recommends against dexamethasone for those hospitalized but not on supplemental oxygen, NIH recommends it for those who need supplemental oxygen, high-flow or noninvasive ventilation, and mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

If dexamethasone isn't available, an alternative corticosteroid such as prednisone, methylprednisolone, or hydrocortisone can be used, NIH says.

Tocilizumab

On June 24, the FDA authorized tocilizumab (Actemra) for the treatment of hospitalized adult and pediatric patients on systemic corticosteroids and supplemental oxygen, non-invasive or mechanical ventilation, or ECMO.

The NIH recommends using tocilizumab in combination with dexamethasone in certain hospitalized COVID patients exhibiting rapid respiratory decompensation. That includes those who have been admitted to the ICU within the previous 24 hours who require invasive mechanical ventilation, noninvasive mechanical ventilation or high-flow nasal cannula oxygen.

Tocilizumab (or baricitinib) can also be used in combination with dexamethasone alone or dexamethasone plus remdesivir in hospitalized patients on high-flow oxygen or noninvasive ventilation who have evidence of clinical progression or increased markers of inflammation.

NIH said there wasn't enough evidence to identify which patients requiring supplemental oxygen therapy might benefit from adding tocilizumab (or baricitinib) to dexamethasone, with or without remdesivir. "Some Panel members would add either baricitinib or tocilizumab to patients who are exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone, but who do not yet require high-flow oxygen or noninvasive ventilation," the guidance states.

The agency says tocilizumab should be avoided for "significantly" immunocompromised patients.

There's no evidence for using other IL-6 inhibitors in COVID-19, but many remain under study.

Baricitinib

On May 27, the NIH said physicians could use baricitinib (or tocilizumab) in combination with dexamethasone alone or dexamethasone plus remdesivir for treating hospitalized patients on high-flow oxygen or noninvasive ventilation who have evidence of clinical progression or increased markers of inflammation.

NIH said there wasn't enough evidence to identify which patients requiring supplemental oxygen therapy would benefit from adding baricitinib (or tocilizumab) to dexamethasone, with or without remdesivir. "Some Panel members would add either baricitinib or tocilizumab to patients who are exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone, but who do not yet require high-flow oxygen or noninvasive ventilation," the guidance states.

Anticoagulation

NIH recommends that all adults hospitalized for COVID-19 who aren't pregnant should receive prophylactic anticoagulation to prevent venous thromboembolism (VTE). (Pregnant patients hospitalized for severe COVID-19 should also get prophylactic anticoagulation unless it's contraindicated.)

The agency notes that there are currently insufficient data to recommend either for or against the use of thrombolytics or higher-than-prophylactic-doses of anticoagulation in hospitalized patients outside of a clinical trial.

Convalescent Plasma

Convalescent plasma has an FDA EUA to treat hospitalized COVID-19 patients. Only high-titer plasma is now authorized, however, and with restriction to hospitalized patients who are early in their disease course or those who have impaired humoral immunity.

For hospitalized patients without impaired immunity, NIH guidelines recommend against plasma for those who are mechanically ventilated and against high-titer plasma for hospitalized patients not on the vent, except in a clinical trial.

As for hospitalized patients with impaired immunity, NIH says there are insufficient data to recommend for or against the therapy. There's also insufficient evidence to make recommendations about plasma in non-hospitalized patients, NIH said.

Monoclonal Antibodies: bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab

In late June, the U.S. government halted distribution of bamlanivimab/etesevimab combination therapy, for lack of efficacy against the Gamma (P.1) and Beta (B.1.351) variants. The FDA had earlier rescinded the EUA for bamlanivimab monotherapy due to its lack of efficacy against variants.

The FDA issued the EUA for casirivimab/imdevimab in November 2020, followed by bamlanivimab/etesevimab in February and sotrovimab in May of this year.

NIH currently recommends against the use of bamlanivimab/etesevimab, while casirivimab/imdevimab and sotrovimab are recommended for non-hospitalized patients with mild to moderate COVID-19 who are at high risk for clinical progression.

In August, the FDA expanded the EUA for casirivimab-imdevimab to also include post-exposure prophylaxis for high-risk people exposed to someone with COVID-19, and can be administered as a subcutaneous injection or intravenous infusion.

Budesonide

In a pragmatic British trial, the inhaled corticosteroid budesonide (Pulmicort) shortened the duration of illness for outpatients at risk for severe disease, and diminished rates of hospitalization or death. The NIH, however, says there's currently insufficient evidence to recommend either for or against the therapy.

Failed or Debated Therapies

Hydroxychloroquine

Both the WHO and the NIH recommend against the use of hydroxychloroquine -- with or without azithromycin -- for the treatment of COVID-19 in both hospitalized and non-hospitalized patients.

Findings from the RECOVERY trial showed that use of hydroxychloroquine did not reduce mortality among COVID-19 patients after 28 days, and in fact trended towards risk of death. Additionally, patients who received the antimalarial drug had a longer median hospital stay than those who received standard of care.

The FDA granted hydroxychloroquine EUA in March 2020, but rescinded it in June following the publication of these findings.

Ivermectin

In January, the NIH changed its recommendation from "against" use of ivermectin in COVID-19 to noting that there are "insufficient data" to recommend for or against the therapy.

The antiparasitic drug has shown some potential to inhibit SARS-CoV-2 replication in cell cultures. However, according to the NIH, achieving the plasma concentrations necessary to achieve the antiviral efficacy detected in vitro would require doses up to 100-fold higher than those approved for use in humans.

NIH also notes several limitations of available randomized trials and retrospective cohort studies, including small sample size, various doses and schedules, open-label design, concomitant medications like hydroxychloroquine and azithromycin, and ill-defined study outcomes.

Vitamin C

NIH states that there are insufficient data to recommend for or against the use of vitamin C (ascorbic acid) in COVID-19.

There are several ongoing clinical trials evaluating the efficacy of vitamin C for treating COVID-19, but few have been completed. A study of 56 hospitalized patients in China found that high-dose intravenous vitamin C was not effective at preventing mechanical ventilation over a 28-day period. Additionally, a randomized controlled trial of vitamin C and zinc showed no impact of either supplement on the course of symptoms in patients with mild illness.

Vitamin D

NIH states that there are insufficient data to recommend for or against the use of vitamin D in COVID-19.

While vitamin D deficiency has been associated with an increased risk of community-acquired pneumonia in older adults and children, no conclusive evidence shows it could be used to fight COVID-19.

In February, a large randomized Brazilian trial published in JAMA found no difference in length of hospital stay for those with moderate to severe COVID-19 given high-dose vitamin D or placebo.

Zinc

NIH states there are insufficient data to recommend for or against the use of zinc in COVID-19. It also recommends against zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial.

Protease Inhibitors

The NIH recommends against using lopinavir/ritonavir and other HIV protease inhibitors to treat COVID-19 in hospitalized and non-hospitalized patients because clinical trials have not shown clinical benefit in COVID patients.

The drugs did not demonstrate efficacy in two large randomized controlled trials of hospitalized patients -- including the RECOVERY trial and the WHO Solidarity Trial.

Colchicine

The NIH recommends against the use of colchicine in hospitalized patients unless they're enrolled in a clinical trial. NIH also says there are insufficient data to recommend for or against the anti-inflammatory drug, which is commonly used to treat gout, in patients who aren't hospitalized.

The colchicine arm of the RECOVERY trial was recently halted because an independent data monitoring committee found the drug wasn't helping hospitalized patients with COVID.

However, top-line results from the COLCORONA trial, which were announced in January via a press release, showed improved outcomes for patients with mild illness from COVID-19.

Fluvoxamine

On April 23, NIH updated its guidance to state that there aren't enough data to recommend for or against the use of this selective serotonin reuptake inhibitor (SSRI) in any stage of COVID-19 treatment.

Two studies of fluvoxamine have garnered attention. A small randomized controlled trial of 152 participants, published in the Journal of the American Medical Association, showed that none of the patients taking fluvoxamine reached the primary endpoint of clinical deterioration compared with 8.3% of those on placebo, and only one required hospitalization compared with 5 in the placebo group.

Another prospective, non-randomized study conducted among workers at a racetrack in California showed a lower hospitalization rate for those who took the drug compared with those who declined.

The studies have significant limits, and MedPage Today found that a Silicon Valley entrepreneur has extensively pushed using fluvoxamine to treat COVID-19.

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