Coronavirus disease 2019 (COVID-19) - Emerging treatments

Nirmatrelvir/ritonavir

Nirmatrelvir is an experimental oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-3CL protease inhibitor antiviral drug. Coadministration with a low dose of ritonavir (which is commonly administered with other protease inhibitors as part of antiretroviral therapy for HIV infection) helps to slow the hepatic metabolism of nirmatrelvir so it remains active in the body for a longer period of time. Nirmatrelvir/ritonavir is authorized for use in some countries. In the UK, nirmatrelvir/ritonavir has been approved for the treatment of mild to moderate disease in adults who are at high risk of developing severe disease.[804] In the US, nirmatrelvir/ritonavir has been granted an emergency-use authorization for the treatment of mild to moderate disease in children ≥12 years of age (weighing ≥40 kg) and adults with a positive result of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe disease including hospitalization or death. It is not authorized for pre-exposure or postexposure prophylaxis, or the treatment of hospitalized patients.[805] In Europe, nirmatrelvir/ritonavir is recommended for adults who do not require supplemental oxygen and who are at increased risk of progressing to severe disease. The European Medicines Agency is currently reviewing an application for authorization.[806] The US National Institutes of Health guidelines panel recommends nirmatrelvir/ritonavir in nonhospitalized patients ≥12 years of age (weighing ≥40 kg) and adults with mild to moderate disease who are at high risk of disease progression. Nirmatrelvir/ritonavir should be initiated as soon as possible after diagnosis and within 5 days of symptom onset. Carefully review the patient’s medication history before starting treatment. Ritonavir-boosted nirmatrelvir has significant and complex drug-drug interactions, primarily due to the ritonavir component of the combination.[371] The Infectious Diseases Society of America recommends nirmatrelvir/ritonavir in ambulatory patients ≥12 years of age (weighing ≥40 kg) and adults with mild to moderate disease who are at high risk for progression to severe disease (low-certainty evidence).[448] Evidence is emerging. According to a press release from the manufacturer, nirmatrelvir/ritonavir was found to reduce the risk of hospitalization or death by 89% (within 3 days of symptom onset) and 88% (within 5 days of symptom onset) compared with placebo in nonhospitalized high-risk adults in the phase 2/3 EPIC-HR randomized double-blind clinical trial. A second study in standard-risk adults is ongoing.[807] Trial results are yet to be published. Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Nirmatrelvir/ritonavir is not recommended in patients with severe renal or hepatic impairment, and it should be used with caution in other patients with renal or hepatic impairment.

Molnupiravir

A prodrug that is metabolized to the ribonucleoside analog N-hydroxycytidine (NHC), which distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP is incorporated into viral RNA by the viral RNA polymerase, resulting in an accumulation of errors in the viral genome leading to inhibition of replication. Molnupiravir is authorized for use in some countries. In the UK, molnupiravir has been approved for the treatment of mild to moderate disease in adults with a positive SARS-CoV-2 diagnostic test and who have at least one risk factor for developing severe disease.[808] In the US, molnupiravir has been granted emergency-use authorization for the treatment of mild to moderate disease in adults with a positive result of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe disease including hospitalization or death, and for whom alternative authorized treatment options are not accessible or clinically appropriate. It is not authorized for pre-exposure or postexposure prophylaxis, or the treatment of hospitalized patients.[809] In Europe, molnupiravir is recommended for adults who do not require supplemental oxygen and who are at increased risk of developing severe disease. The European Medicines Agency is currently reviewing an application for authorization.[810] The UK National Institute for Health and Care Excellence currently offers no recommendation on the use of molnupiravir.[450] However, a UK-wide clinical commissioning policy recommends molnupiravir in eligible patients ≥18 years of age who are within 5 days of symptom onset if casirivimab/imdevimab is contraindicated or treatment with a monoclonal antibody is not possible.[811] The US National Institutes of Health guidelines panel recommends molnupiravir in nonhospitalized patients ≥18 years of age with mild to moderate disease who are at high risk of disease progression, when no other options can be used. Molnupiravir should be initiated as soon as possible after diagnosis and within 5 days of symptom onset.[371] The Infectious Diseases Society of America recommends molnupiravir in ambulatory patients ≥18 years of age with mild to moderate disease who are at high risk for progression to severe disease and who have no other treatment options (low-certainty evidence). Patients with mild to moderate disease who are at high risk of progression to severe disease admitted to the hospital for reasons other than COVID-19 may also receive molnupiravir. Patients who put a higher value on the putative mutagenesis, adverse effects, or reproductive concerns, and a lower value on the uncertain benefits, may reasonably decline molnupiravir.[448] Evidence is emerging. Approval in the UK was based on the MOVe-OUT trial. According to a press release from the manufacturer, molnupiravir significantly reduced the risk of hospitalization or death in the 29 days after use in at-risk, nonhospitalized, unvaccinated adults with mild to moderate disease in an analysis of the phase 3 MOVe-OUT trial (1433 patients). Molnupiravir reduced the relative risk of hospitalization or death by approximately 30% (absolute risk reduced from 9.7% to 6.8%).[812] The study did not include children or pregnant women. Recruitment into the study was stopped early due to these positive results. Final trial results are yet to be peer reviewed and published, but an interim analysis of earlier data has been published.[813] Two phase 1 double-blind, randomized, placebo-controlled trials showed that molnupiravir was safe and tolerable without any serious adverse effects. A phase 2 study found that molnupiravir significantly lowered time to viral clearance in patients with mild to moderate disease compared with placebo. However, it was not effective in moderate to severe disease. Several phase 3 trials are ongoing. There are no data evaluating the role of molnupiravir in breakthrough infections following vaccination.[814] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. Women of childbearing potential should use effective contraception for the duration of treatment and for 4 days after the last dose. Men of reproductive potential who are sexually active with women of childbearing potential should abstain from sex or use a reliable method of contraception for the duration of treatment and for at least 3 months after the last dose of molnupiravir. Molnupiravir is is not recommended during pregnancy as animal studies have shown reproductive toxicity; however, pregnant women may reasonably choose to use molnupiravir if no other treatments are available, after being informed of the potential risks. Breastfeeding is not recommended during treatment and for 4 days after the last dose. Molnupiravir has not been authorized for use in patients <18 years of age as it may affect bone and cartilage growth.

Janus kinase inhibitors

Janus kinase inhibitors are thought to prevent the dysregulated production of proinflammatory cytokines in patients with severe or critical disease. Drugs within this class include baricitinib, tofacitinib, fedratinib, and ruxolitinib. Baricitinib has been granted an emergency-use authorization in the US for the treatment of suspected or confirmed disease in hospitalized children ages 2 years and older and adults who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (with or without remdesivir).[815] It has not been authorized for this indication in the UK or Europe; however, the European Medicines Agency is currently evaluating its use in hospitalized patients from 10 years of age who require supplemental oxygen.[816] Other Janus kinase inhibitors are not authorized for use in patients with COVID-19 as yet. The US National Institutes of Health guidelines panel recommends baricitinib, in combination with dexamethasone alone or dexamethasone plus remdesivir, in recently hospitalized patients on high-flow oxygen or noninvasive ventilation with rapidly increasing oxygen needs and systemic inflammation. The panel recommends against the use of baricitinib in combination with tocilizumab except in the context of a clinical trial. There is potential for an additive risk of infection. There is insufficient evidence to recommend either for or against the use of baricitinib in children. The panel recommends tofacitinib may be used as an alternative if baricitinib is not available or it is not feasible to use it.[371] The Infectious Diseases Society of America suggests baricitinib in hospitalized adults with severe disease who have elevated inflammatory markers. The panel suggests tofacitinib in hospitalized adults with severe disease who are not on noninvasive or invasive mechanical ventilation. Baricitinib is recommended for up to 14 days or until discharge from hospital. It appears to demonstrate the most benefit in those on high-flow oxygen or noninvasive ventilation at baseline. Limited additional data suggest a mortality reduction even among patients requiring mechanical ventilation. The guideline panel suggests baricitinib with remdesivir, rather than remdesivr alone, in patients who cannot receive a corticosteroid because of a contraindication. Tofacitinib appears to demonstrate the most benefit in those on supplemental or high-flow oxygen. Patients treated with tofacitinib should be on at least prophylactic-dose anticoagulation. Patients who receive baricitinib or tofacitinib should not receive an interleukin-6 inhibitor.[448] Evidence is emerging. Emergency-use authorization of baricitinib was based on a randomized, double-blind, placebo-controlled trial that found baricitinib plus remdesivir reduced time to recovery (defined as either being discharged from the hospital, or being hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care) within 29 days after initiating treatment compared with patients who received placebo plus remdesivir. The median time to recovery was 7 days for baricitinib plus remdesivir and 8 days for placebo plus remdesivir.[817] A living systematic review and network meta-analysis found that Janus kinase inhibitors may reduce the need for mechanical ventilation (low-certainty evidence) and probably reduce the duration of mechanical ventilation (moderate-certainty evidence) compared with standard care.[756][757] Another systematic review and network meta-analysis found that Janus kinase inhibitors are also associated with a reduced risk of mortality, and clinical improvement in hospitalized patients.[818] A systematic review and meta-analysis found that baricitinib reduced the rate of intensive care admission, requirement for invasive ventilation, and mortality.[819] A meta-analysis that included six cohort studies and five clinical trials involving over 2000 participants treated with either baricitinib or ruxolitinib found that use of Janus kinase inhibitors reduced the need for invasive mechanical ventilation and increased survival, but did not reduce the length of hospitalization. The evidence was most convincing for baricitinib. Timing of treatment may be important in determining the impact on outcomes.[820] A meta-analysis that included four randomized controlled trials and 1300 participants found that treatment with a Janus kinase inhibitor in addition to standard of care reduced the risk of death by 43%, and mechanical ventilation or ECMO by 36% compared with control.[821] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug. The US Food and Drug Administration has issued a warning about increased risk of serious heart-related events, cancer, blood clots, and death with certain JAK inhibitors.[822]

Anakinra

Anakinra is an intravenous/subcutaneous interleukin-1 inhibitor. It is being trialed in patients for the treatment of SARS-CoV-2-induced cytokine release syndrome. Anakinra is already approved in some countries for certain conditions, but is off-label for this indication. The European Medicines Agency has approved anakinra in adults with pneumonia who require low- or high-flow supplemental oxygen and who are at risk of developing severe respiratory failure, as determined by blood soluble urokinase plasminogen activator receptor (suPAR) levels of at least 6 nanograms/mL.[823] The UK National Institute for Health and Care Excellence states that there is no evidence available to determine whether anakinra is effective, safe, or cost-effective for treating adults and children with secondary hemophagocytic lymphohistiocytosis triggered by SARS-CoV-2 or a similar coronavirus.[824] The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of anakinra.[371] Evidence is emerging. A systematic review and meta-analysis of nine studies (eight observational studies and one randomized controlled trial) found that anakinra significantly reduced mortality in hospitalized patients with moderate to severe disease. Subgroup analysis identified patients with C-reactive protein levels >100 mg/L may benefit most.[825] A systematic review and meta-analysis of nine observational studies found that anakinra reduced the need for invasive mechanical ventilation and mortality risk in hospitalized nonintubated patients compared with standard of care.[826] A systematic review and meta-analysis of 15 studies (five observational studies, five case series, four case reports, and one randomized controlled trial) also found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality risk compared with standard care alone.[827] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Colchicine

Colchicine is an anti-inflammatory agent that downregulates multiple pro-inflammatory pathways. It is thought that its inhibitory effects on neutrophil activity, cytokine generation, and the inflammation/thrombosis interface, along with an overall lack of evidence for systemic immunosuppression, make it a useful treatment.[828] Colchicine is already approved in some countries for indications such as gout and familial Mediterranean fever, but is off-label for this indication. The UK National Institute for Health and Care Excellence does not recommend the use of colchicine. Evidence in hospitalized patients and community settings found no benefit of effect on hospitalization, recovery time, all-cause mortality, mechanical ventilation, clinical progression, intensive care unit admission, or hospital discharge within 28 days.[450] The US National Institutes of Health guidelines panel recommends against the use of colchicine for the treatment of hospitalized patients, and against its use in nonhospitalized patients except in the context of a clinical trial.[371] Evidence does not currently support the use of this treatment. A living systematic review and network meta-analysis found that colchicine may reduce mortality (low-certainty evidence) and probably reduces the duration of hospitalization (low-certainty evidence) compared with standard care.[756][757] The largest meta-analysis to date (approximately 16,000 patients), which included six randomized controlled trials, found that colchicine did not significantly reduce mortality, need for ventilatory support, intensive care unit admission, or length of hospital stay compared with supportive care only, and patients taking colchicine had a higher risk of adverse events. The GRADE quality of evidence was moderate for most outcomes.[829] The UK RECOVERY trial found that colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death in hospitalized adults.[830] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors

GM-CSF inhibitors (e.g., lenzilumab, mavrilimumab, otilimab) may mitigate lung inflammation in severe and critical disease by minimizing downstream production of numerous pro-inflammatory mediators involved in the pathogenesis of disease. These agents are currently investigational. The US Food and Drug Administration has declined an emergency-use authorization for lenzilumab to treat hospitalized COVID-19 patients as it was unable to conclude that the known and potential benefits of lenzilumab outweigh the known and potential risks of its use.[831] The UK Medicines and Healthcare products Regulatory Agency is currently reviewing an application for a conditional marketing authorization for lenzilumab. The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of GM-CSF inhibitors.[371] Evidence is emerging. A phase 3, randomized, double-blind, placebo-controlled trial found that lenzilumab significantly improved survival without invasive mechanical ventilation to day 28 in hospitalized patients.[832] A small multicenter, double-blind, randomized, placebo-controlled trial found that there was no significant difference in the proportion of patients with severe disease, hypoxemia, and systemic hyperinflammation who were free of supplemental oxygen at day 14 after treatment with mavrilimumab compared with placebo.[833]

Convalescent plasma

Convalescent plasma is a blood product that contains antibodies to SARS-CoV-2 from patients who have recovered. High-titer convalescent plasma (i.e., plasma with high SARS-CoV-2 antibody titers) has been granted an emergency-use authorization in the US for the treatment of hospitalized patients early in the disease course, and to those hospitalized patients who have impaired humoral immunity and cannot produce an adequate antibody response. Low-titer convalescent plasma is no longer authorized.[834] It has not been authorized for this indication in the UK or Europe. The World Health Organization recommends against the use of convalescent plasma. The guideline recommends against using convalescent plasma in patients with nonsevere disease. In these patients, convalescent plasma did not result in an important impact on mortality, based on high-certainty evidence. Convalescent plasma probably did not impact mechanical ventilation, based on moderate-certainty evidence. There were no data evaluating the risk of hospitalization and therefore the impact is very uncertain. The guideline recommends against using convalescent plasma in patients with severe or critical disease, except in the context of a clinical trial. In these patients, convalescent plasma may not result in an important impact on mortality, mechanical ventilation, time to symptom improvement, length of hospital stay, or ventilator-free days, based on low-certainty evidence.[710][711][712] UK guidance recommends that convalescent plasma should not be used in the management of hospitalized patients with suspected or confirmed infection.[835] The US National Institutes of Health guidelines panel recommends against the use of convalescent plasma in hospitalized patients without impaired humoral immunity. There is insufficient evidence to recommend either for or against the use of convalescent plasma in: nonhospitalized patients without impaired humoral immunity; and nonhospitalized or hospitalized patients with impaired humoral immunity. Use in hospitalized children with impaired immunity may be considered on a case-by-case basis provided that they meet the emergency-use authorization criteria.[371] The Infectious Diseases Society of America recommends against the use of convalescent plasma in hospitalized patients, based on moderate-certainty evidence. The guideline panel suggests against convalescent plasma in ambulatory patients with mild to moderate disease outside of the context of a clinical trial.[448] Evidence does not currently support the use of this treatment. A living systematic review and network meta-analysis found that convalescent plasma may not confer any meaningful benefit in patients with any disease severity. Whether or not high-titer convalescent plasma confers any benefit remains uncertain.[719] A Cochrane review found high-certainty evidence that convalescent plasma does not reduce mortality and has little to no impact on measures of clinical improvement for the treatment of moderate to severe disease.[836] Evidence from meta-analyses is conflicting. While some meta-analyses found that treatment with convalescent plasma was not significantly associated with a decrease in all-cause mortality (or any benefit for other outcomes) compared with placebo or standard of care, others have found a reduction in mortality, especially when trials with low-titer convalescent plasma were removed from the analyses.[837][838][839][840][841][842] The UK RECOVERY trial found that high-titer convalescent plasma did not improve 28-day mortality or other prespecified outcomes (hospital discharge within 28 days, progression to invasive mechanical ventilation) in hospitalized patients compared with usual care.[843] Emergency-use authorization in the US was based on the preprint (not peer reviewed) publication of an open-label, multicenter, expanded access program study of over 35,000 patients that found convalescent plasma lowered 7-day mortality by 9% in hospitalized patients when given within 3 days of diagnosis, and by 12% when given 4 or more days later.[844]

Intravenous immune globulin

Intravenous immune globulin (IVIG) is a blood product prepared from serum pooled from healthy donors. It has an immunomodulatory effect that suppresses a hyperactive immune response. IVIG is already approved in some countries for certain conditions, but is off-label for this indication. The US National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against the use of anti-SARS-CoV-2 specific immune globulin.[371] Evidence does not currently support the use of this treatment. A living systematic review and network meta-analysis found that IVIG may not confer any meaningful benefit in patients with any disease severity.[719] A meta-analysis of four clinical trials and three cohort studies with 825 hospitalized patients found that IVIG reduced mortality in patients with critical disease; however, there was no significant difference between the severe and nonsevere subgroups.[845] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Stem cell therapy

Mesenchymal stem cells are an investigational product and have been studied for their immunomodulatory properties. It is thought that they can reduce the pathologic changes that occur in the lungs, and inhibit the cell-mediated immune inflammatory response.[846] Mesenchymal stem cells are not approved for this indication. The US National Institutes of Health guidelines panel recommends against the use of mesenchymal stem cells except in the context of a clinical trial.[371] Evidence is emerging. Systematic reviews and meta-analyses have found that mesenchymal stem cell therapy significantly reduces the incidence of adverse events and mortality.[847][848] Remestemcel-L (ex vivo cultured adult human mesenchymal stem cells from the bone marrow of healthy adult donors) is currently in phase 3 trials for the treatment of moderate to severe acute respiratory distress syndrome in ventilator-dependent patients. An interim analysis of data found that the trial is not likely to meet its 30-day mortality reduction end point and has stopped enrollment, although the trial will be completed with the patients currently enrolled, with follow-up as planned.[849]

Interferons

Interferons are a family of cytokines with antiviral properties. Interferons are already approved in some countries for certain conditions, but are off-label for this indication. The US National Institutes of Health guidelines panel recommends against the use of interferons for the treatment of hospitalized patients except in the context of a clinical trial. The panel recommends against the use of interferon beta for the treatment of hospitalized patients. The panel recommends against the use of interferon alfa or lambda for the treatment of hospitalized patients, except in the context of a clinical trial. The panel recommends against the use of interferon for the treatment of nonhospitalized patients with mild to moderate disease, except in the context of a clinical trial.[371] Evidence does not currently support the use of this treatment. The WHO Solidarity trial found that interferon beta-1a appears to have little or no effect on hospitalized patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[752] A randomized, placebo-controlled, phase 2 trial found that nebulized interferon beta-1a was associated with a higher odds of clinical improvement and more rapid recovery.[850] A phase 2 trial found that peginterferon lambda reduced viral load and increased the number of participants with a negative nasopharyngeal swab at day 7 in outpatients with mild to moderate disease compared with placebo.[851][852] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing these drugs.

Ivermectin

Ivermectin is a broad-spectrum antiparasitic agent. It has been shown to be effective against SARS-CoV-2 in vitro.[853] Ivermectin is already approved in some countries for parasitic infections, but is off-label for this indication. The World Health Organization does not recommend ivermectin except in the context of a clinical trial.[710] This recommendation applies to patents with any disease severity and any duration of symptoms. There is insufficient evidence to be clear to what extent, if any, ivermectin is helpful or harmful in treating COVID-19.[711][712] For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalization, and viral clearance, the evidence is of very low certainty. The UK National Institute for Health and Care Excellence does not recommend ivermectin except as part of a clinical trial.[450] The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of ivermectin.[371] The Infectious Diseases Society of America suggests against the use of ivermectin in outpatients and hospitalized patients outside of the context of a clinical trial.[448] Evidence is emerging. A Cochrane review found no evidence to support the use of ivermectin for treating or preventing infection, but the evidence base was limited (as of 26 May 2021). The safety and efficacy of ivermectin was uncertain based on very low- to low-certainty evidence. Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention outside of well‐designed randomized trials.[854] Data from meta-analyses are conflicting. A meta-analysis of 24 randomized controlled trials with 3400 participants found moderate-certainty evidence that ivermectin provided a significant survival benefit when used for treatment. Low-certainty evidence supports a likely clinical benefit in terms of improvement and deterioration. Low-certainty evidence also suggests a significant effect in prophylaxis. Overall, the evidence suggested that early use may reduce morbidity and mortality.[855] Other meta-analyses also support an improvement in clinical outcomes with use of ivermectin, although the quality of evidence is very low to low.[856][857] [858][859][860] However, there are other meta-analyses that found that ivermectin did not reduce all-cause mortality, length of hospital stay, incidence of mechanical ventilation, time to clinical recovery, or respiratory viral clearance.[860][861][862][863] One meta-analysis found that ivermectin was effective when used for pre-exposure prophylaxis in preventing transmission among healthcare workers in low- and middle-income countries; however, evidence was limited.[864] The PRINCIPLE trial in the UK is currently investigating the use of ivermectin.[865] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Nitazoxanide

Nitazoxanide is a broad-spectrum antiparasitic agent with in vitro activity against SARS-CoV-2 that is already approved in some countries for indications such as cryptosporidiosis and giardiasis, but is off-label for this indication. The US National Institutes of Health guidelines panel recommends against the use of nitazoxanide except in the context of a clinical trial.[371] Evidence is emerging. A randomized, double-blind pilot trial found an evident decrease in the time for hospital discharge, faster evolution to reverse transcription polymerase chain reaction negativity, and a higher reduction of inflammatory markers among patients treated with nitazoxanide compared with placebo. However, this was a small, proof-of-concept trial.[866] A multicenter, randomized, double-blind, placebo-controlled trial in adults with mild disease found that nitazoxanide was associated with reduced viral load but not reduced time to symptom resolution.[867] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Fluvoxamine

Fluvoxamine is a selective serotonin-reuptake inhibitor that has anti-inflammatory and possible antiviral effects.[868] Fluvoxamine is already approved in some countries for indications such as depression and obsessive compulsive disorder, but is off-label for this indication. The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of fluvoxamine.[371] The Infectious Diseases Society of America recommends fluvoxamine in ambulatory patients only in the context of a clinical trial.[754] Evidence is emerging. The TOGETHER trial, a randomized placebo-controlled trial with nearly 1500 participants, found that fluvoxamine reduced the need for hospitalization (5% absolute risk reduction) among high-risk patients compared with placebo.[869] A preliminary double-blind, randomized controlled trial found that adult outpatients had a lower likelihood of clinical deterioration over 15 days compared with placebo; however, the study was limited by a small sample size and short follow-up duration.[870] A prospective cohort study in the setting of a mass outbreak found that fluvoxamine may prevent clinical deterioration requiring hospitalization and symptoms persisting beyond 2 weeks.[871] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Inhaled corticosteroids

Inhaled budesonide is undergoing clinical trials and shows promise.[872] It is already approved in some countries for indications such as asthma and COPD, but is off-label for this indication. The UK National Institute for Health and Care Excellence only recommends inhaled budesonide as part of a clinical trial. Trial evidence suggests some benefit in reducing time to recovery. However, evidence suggests there is no statistically significant difference for the outcomes of hospitalization and death, or need for mechanical ventilation in people having inhaled budesonide and usual care compared with usual care alone. Evidence is limited and further research is required.[450] The US National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of inhaled budesonide.[371] Evidence is emerging. The PRINCIPLE trial has reported a 3-day median benefit in self-reported recovery for patients in the community setting who are at higher risk of complications and who received inhaled budesonide.[873] The impact on hospitalization rates or mortality has not been established. Other randomized controlled trials have found that inhaled ciclesonide did not show a statistically significant increase in time to resolution of symptoms compared with placebo.[874][875] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing this drug.

Antibiotics

Azithromycin is a macrolide antibiotic, and doxycycline is a tetracycline antibiotic. Both are approved for use in various bacterial infections. The UK National Institute for Health and Care Excellence does not recommend the use of azithromycin or doxycycline. The guideline panel considered that the results from studies of azithromycin for moderate to critical disease in the hospital setting and mild to moderate disease in the community setting showed no meaningful benefit in any of the critical outcomes. [450] The UK Medicines and Healthcare products Regulatory Agency recommends that azithromycin and doxycycline should not be used within primary care (or hospitalized patients for azithromycin) unless there are additional indications for which their use remains appropriate.[876] The US National Institutes of Health guidelines panel recommends against the use of antibacterial therapy (e.g., azithromycin, doxycycline) in the absence of another indication.[371] Evidence does not support the use of this treatment. Systematic reviews and meta-analyses have found that azithromycin was not associated with an improvement in hospitalization rate, intensive care unit admission, need for respiratory support, or mortality rate compared with control.[877][878] The overall quality of evidence was low to very low. The UK RECOVERY trial found that azithromycin showed no significant clinical benefit (i.e., length of hospital stay, need for invasive mechanical ventilation, 28-day mortality) in hospitalized patients compared with usual standard care alone.[879] The UK PRINCIPLE trial found that doxycycline use was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths in patients with suspected disease in the community who were at high risk of adverse outcomes.[880] The ATOMIC2 open-label randomized trial found that adding azithromycin to standard of care treatment in nonhospitalized patients with mild to moderate disease did not reduce the risk of subsequent hospital admission or death.[881] An interim analysis of the trial concluded that azithromycin and doxycycline offered no meaningful beneficial effect, in terms of time to recovery, hospitalization, or death compared with standard of care in patients ages 50 years and over who were treated at home in the early stages of infection.[876][882] Consult local drug formulary for information about contraindications, cautions, adverse effects, and drug interactions before prescribing these drugs.

Vitamin D

Vitamin D supplementation has been associated with a reduced risk of acute respiratory infections such as influenza.[883][884][885][886] The US National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against vitamin D for the treatment or prevention of COVID-19.[371] The UK National Institute for Health and Care Excellence recommends vitamin D supplementation in adults (including pregnant and breastfeeding women), young people, and children over 4 years of age between October and early March (and at other times of the year if at risk of vitamin D deficiency) to maintain bone and muscle health. However, it does not recommend supplementation to solely prevent or treat COVID-19, except as part of a clinical trial.[887] Evidence is emerging. A Cochrane review found there is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation. The evidence is very uncertain. There was substantial clinical and methodological heterogeneity of included studies, mainly due to different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes.[888] Meta-analyses found that vitamin D might be associated with improved clinical outcomes, including decreased risk of intensive care admission and mortality, and that there may be a potential role for vitamin D supplementation in reducing disease severity, but noted that additional evidence is required.[889][890][891][892] The evidence is currently insufficient to support the routine use of vitamin D as its effectiveness appears to depend on the dose used, baseline vitamin D levels, and the severity of disease.[893] A pilot randomized controlled trial found that high-dose calcifediol significantly reduced the need for intensive care unit treatment in hospitalized patients, and may improve clinical outcomes.[894]

Vitamin C

Vitamin C supplementation has shown promise in the treatment of viral infections.[895] High-dose intravenous vitamin C is being trialed in some centers for the treatment of severe disease.[896] The US National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against vitamin C for the treatment of noncritically ill or critically ill patients.[371] Evidence is emerging. A systematic review of six randomized controlled trials found that vitamin C did not reduce mortality, length of stay in hospital or intensive care unit, or need for invasive mechanical ventilation. However, there were various limitations to the study (e.g., heterogeneity of dose and route). Further well-designed randomized controlled trials are required.[897] A systematic review and meta-analysis found that length of hospital stay and mortality was not significantly different between patients taking high-dose intravenous vitamin C and those not taking it. Evidence supporting the therapeutic use of high-dose intravenous vitamin C is lacking and further studies are required.[898]

Clinical trials

Various other treatments are in clinical trials around the world. Global coronavirus COVID-19 clinical trial tracker International trials to identify treatments that may be beneficial, such as the World Health Organization’s Solidarity trial, and the UK’s randomized evaluation of COVID-19 therapy (RECOVERY) trial, are ongoing. RECOVERY trial WHO: COVID-19 “Solidarity” therapeutics trial