Under the ferocious onslaught of COVID-19, there’s been a scramble not only to find new medicines but to repurpose old ones, writes MedicalBrief. Not all have been as controversial as Ivermectin or soared only to be dumped as quickly as hydroxychloroquine. MedPage Today has compiled an invaluable ready-reference for the embattled doctor.
The live list of currently authorised and/or validated therapies, notes the stage of disease for which they work best as well as others that didn't pan out or are still under evaluation.
Treatments in use
Remdesivir (Veklury), an antiviral, is currently the only Food & Drug Administration (FDA)-approved therapy for COVID-19. It was approved in October 2020 for hospitalised COVID-19 patients aged 12 and up who weigh at least 40kg. Its original emergency use authorisation (EUA) has been revised to also allow for treatment of hospitalised paediatric patients under 12 who weigh at least 3.5kg.
FDA also issued an EUA for the combination of remdesivir plus the oral JAK inhibitor baricitinib (Olumiant) in hospitalised patients with severe COVID-19. (See baricitinib section below.)
The National Institute of Health (NIH) guidelines recommend the use of remdesivir in hospitalised 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, a corticosteroid with potent anti-inflammatory effects, is recommended for use in many categories of patients hospitalised with COVID-19, but not for those with mild-to-moderate disease who aren't in hospital. While it recommends against dexamethasone for those in hospital but not on supplemental oxygen, NIH recommends it for those who need supplemental oxygen, high-flow or non-invasive 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.
On June 24, the FDA authorised tocilizumab (Actemra) for the treatment of hospitalised adult and paediatric 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 hospital 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, non-invasive 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 hospitalised patients on high-flow oxygen or non-invasive 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.
On May 27, the NIH said physicians could use baricitinib (or tocilizumab) in combination with dexamethasone alone or dexamethasone plus remdesivir for treating hospital patients on high-flow oxygen or non-invasive 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.
NIH recommends that all adults hospitalised for COVID-19 who aren't pregnant should receive prophylactic anticoagulation to prevent venous thromboembolism (VTE). (Pregnant patients hospitalised 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 hospitalised patients outside a clinical trial.
Convalescent plasma has an FDA EUA to treat hospitalised COVID-19 patients. Only high-titer plasma is now authorised, however, and with restriction to hospitalised patients who are early in their disease course or those who have impaired humoral immunity.
For hospital patients without impaired immunity, NIH guidelines recommend against plasma for those who are mechanically ventilated and against high-titer plasma for hospitalised patients not on the vent, except in a clinical trial. As for hospitalised 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-hospitalised patients, NIH said.
Monoclonal antibodies: bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab
In late June, the US 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 this year. All are indicated for mild-to-moderate COVID-19 in adults and paediatric patients who are at high risk of progressing to severe disease.
The NIH currently recommends all three products in its clinical guidelines, but notes that its monoclonal antibody page is currently under revision. The agency's recommendations generally track with the indications listed in the products' EUAs.
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 hospitalisation or death. The NIH, however, has yet to weigh in on the therapy.
Failed or debated therapies
Both the World Health Organisation (WHO) and the NIH recommend against the use of hydroxychloroquine, with or without azithromycin, for the treatment of COVID-19 in both hospitalised and non-hospitalised 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.
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 randomised 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.
NIH states 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 hospitalised patients in China found that high-dose intravenous vitamin C was not effective at preventing mechanical ventilation over a 28-day period. Additionally, a randomised controlled trial of vitamin C and zinc showed no impact of either supplement on the course of symptoms in patients with mild illness.
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 randomised 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.
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.
The NIH recommends against using lopinavir/ritonavir and other HIV protease inhibitors to treat COVID-19 in hospitalised and non-hospitalised patients because clinical trials have not shown clinical benefit in COVID patients. The drugs did not demonstrate efficacy in two large randomised controlled trials of hospitalised patients, including the RECOVERY trial and the WHO Solidarity Trial.
The NIH recommends against the use of colchicine in hospitalised 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 hospitalised. The colchicine arm of the RECOVERY trial (the world’s largest clinical trial into treatments for COVID-19, with more than 30,000 participants across 177 trial sites in the UK) was recently halted because an independent data monitoring committee found the drug wasn't helping hospitalised 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.
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 randomised 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 hospitalisation compared with five in the placebo group. Another prospective, non-randomised study conducted among workers at a racetrack in California showed a lower hospitalisation 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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