Emerging treatments

Introduction

Various treatments for COVID-19 are in clinical trials around the world. There are several treatments being used off-label on a compassionate-use basis, or as part of a clinical trial. It is important to note that there may be serious adverse effects associated with these drugs, and that these adverse effects may overlap with the clinical manifestations of COVID-19. These drugs may also increase the risk of death in an older patient or a patient with an underlying health condition (e.g., drugs that prolong the QT interval may increase the risk of cardiac death).[761] Drug-drug interactions with the patient’s existing medication(s), and drug-disease interactions (e.g., impact of inflammation on drug metabolism in COVID-19 patients), must also be considered.[762] International trials to identify treatments that may be beneficial, such as the World Health Organization’s (WHO) Solidarity trial (the world’s largest randomised controlled trial on COVID-19 therapeutics across 30 countries), and the UK’s randomised evaluation of COVID-19 therapy (RECOVERY) trial, are ongoing.

Remdesivir

Remdesivir is a broad-spectrum investigational antiviral agent. There are conflicting recommendations across international guidelines about the use of remdesivir, so it is important that you check local guidance and protocols. Remdesivir may not reduce mortality (low-certainty evidence) or time to symptom resolution (moderate-certainty evidence) compared with standard of care.[598][599]

The WHO recommends against the use of remdesivir in hospitalised patients in addition to standard care, regardless of disease severity. This is a weak or conditional recommendation.[553][597] The recommendation is based on a systematic review and network meta-analysis of four randomised trials with 7333 hospitalised patients, and included the NIAID-ACTT-1 trial (on which the original US approval of remdesivir was based) and the WHO Solidarity trial. There is currently no evidence that remdesivir improves patient outcomes such as time to clinical improvement, the need for mechanical ventilation, or mortality. However, the meta-analysis did not prove that remdesivir has no benefit.[597] The WHO Solidarity trial found that remdesivir appears to have little or no effect on hospitalised patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[763]

Recommendations and evidence for the use of remdesivir in hospitalised patients with COVID-19[Figure caption and citation for the preceding image starts]: Recommendations and evidence for the use of remdesivir in hospitalised patients with COVID-19BMJ. 2020;370:m3379 [Citation ends].

In the US, the National Institutes of Health guidelines panel recommends remdesivir in hospitalised patients who require supplemental oxygen. It may be given alone (e.g., for patients who require minimal supplemental oxygen) or in combination with dexamethasone (e.g., for patients who require increasing amounts of supplemental oxygen). The panel also recommends remdesivir, in combination with dexamethasone, in hospitalised patients who require high-flow oxygen or non-invasive ventilation. It does not recommend remdesivir in patients who require invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). The panel acknowledges that remdesivir may also be appropriate in hospitalised patients who do not require oxygen, but who are at high risk of disease progression. The recommended treatment course is 5 days or until hospital discharge, whichever comes first. Some experts recommend a 10-day course in patients who have not shown substantial clinical improvement by day 5.[3]

The Infectious Diseases Society of America recommends remdesivir (5 days in patients on oxygen and 10 days in patients on mechanical ventilation or ECMO) over no antiviral treatment in hospitalised patients with severe disease based on moderate-certainty evidence. The panel recommends against the routine use of remdesivir in hospitalised patients who do not require oxygen and have an oxygen saturation >94% on room air, based on very low-certainty evidence.[601]

The American College of Physicians recommends the use of remdesivir in hospitalised patients with moderate disease. This recommendation is based on low-certainty evidence that suggests remdesivir may slightly reduce mortality and serious adverse events, reduce time to clinical improvement and recovery, and reduce the need for invasive mechanical ventilation or ECMO compared with standard of care.[764][765]

In the UK and Europe, remdesivir is conditionally approved in adolescents ≥12 years of age and adults with pneumonia who require supplemental oxygen (usually classified as severe disease).[766] However, the European Medicines Agency is reviewing the data from the WHO to see whether any changes are needed to the European marketing authorisation, and has recommended a change to the marketing authorisation to clarify it should only be used in patients on low- or high-flow oxygen or other non-invasive ventilation at start of treatment.[767][768]

The US Food and Drug Administration (FDA) has approved remdesivir for the treatment of COVID-19 in hospitalised children (≥12 years of age and ≥40 kg) and adults. The approval does not cover the entire population that had previously been authorised under the original emergency-use authorisation. The emergency-use authorisation has now been revised to authorise use of remdesivir in hospitalised children who weigh between 3.5 kg and 40 kg, and children <12 years of age who weigh at least 3.5 kg.[769]

Remdesivir can cause gastrointestinal symptoms, elevated transaminase levels, and an increase in prothrombin time. Hypersensitivity reactions have also been reported during and following administration. Remdesivir should not be used in patients with an estimated glomerular filtration rate <30 mL/minute, and it should be used with caution in patients with hepatic impairment. Safety and efficacy has not been evaluated in pregnant women, breastfeeding women, or children. Remdesivir should not be withheld from pregnant women if otherwise indicated. Remdesivir may interact with hydroxychloroquine/chloroquine, but is thought to be safe with corticosteroids.[3] The European Medicines Agency has started a review of a safety signal to assess reports of acute kidney injury in some patients. At this stage, it has not been determined whether there is a causal relationship between remdesivir and acute kidney injury.[770]

Interleukin-6 (IL-6) inhibitors

IL-6 inhibitors (e.g., tocilizumab, siltuximab) are being trialled in patients for the treatment of virus-induced cytokine release syndrome. These drugs are already approved in some countries for other indications. There are conflicting recommendations across international guidelines about the use of these agents, so it is important that you check local guidance and protocols.

UK guidance recommends considering tocilizumab (or sarilumab as an alternative) in critically ill adults admitted to the intensive care unit with severe pneumonia requiring respiratory support when infection is confirmed by microbiological testing (or where a multidisciplinary team has a high level of confidence that the clinical and radiological features suggest that COVID-19 is the most likely diagnosis) and patients do not meet specific exclusion criteria.[771] This recommendation is based on evidence (yet to be peer reviewed) from the REMAP-CAP trial that showed a reduction in mortality of 24% when these drugs were given within 24 hours of intensive care unit admission, compared with standard of care (including corticosteroids). The treatment also reduced the time patients spent in the intensive care unit by more than 1 week on average. The effect is thought to be supplementary to those from corticosteroids.[772] It is possible that any benefit from tocilizumab is seen only in the most severely ill patients when it is given soon after organ support is started, when any developing organ dysfunction may be more reversible.[773]

In the US, the National Institutes of Health guidelines panel recommends against the use of IL-6 inhibitors for the treatment of COVID-19 except in the context of a clinical trial.[3] Likewise, the Infectious Diseases Society of America recommends against the routine use of tocilizumab in hospitalised patients based on low-certainty evidence.[601]

A living systematic review and meta-analysis found that (as of 8 October 2020) there is moderate-certainty evidence that tocilizumab reduces the risk of mechanical ventilation in hospitalised patients. Low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality.[774] The randomised controlled phase 3 EMPACTA trial found that tocilizumab reduced the need for mechanical ventilation in hospitalised patients compared with placebo, although there was no statistical difference in mortality between the two arms.[775] However, the randomised controlled phase 3 COVACTA trial failed to meet its primary end point of clinical status, and found that tocilizumab did not improve mortality.[776] Full results of both trials are yet to be published. Other randomised trials also give conflicting results.[777][778][779][780][781]

Monoclonal antibodies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies have the potential to be used for prophylaxis and treatment of COVID-19. These antibodies bind to the SARS-CoV-2 surface spike protein receptor-binding domain, which blocks the binding of the virus to the angiotensin-converting enzyme-2 (ACE2) host cell surface receptor.[782]

The combination of casirivimab and imdevimab (formerly known as REGN-COV2) has been issued an emergency-use authorisation by the FDA for the treatment of mild to moderate disease in children and adults. The authorisation covers patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe disease and/or hospitalisation. This includes patients who are 65 years of age or older, or who have certain chronic medical conditions. The authorisation was based on a randomised, double-blind, placebo-controlled trial in non-hospitalised adults with mild to moderate symptoms. The trial found that the monoclonal antibody combination reduced COVID-19-related hospitalisation or accident and emergency department visits in patients at high risk for disease progression within 28 days after treatment, when compared with placebo. The study is yet to be published.[783] An interim analysis of an ongoing, randomised, double-blind, phase 1-3 trial in non-hospitalised patients found that casirivimab/imdevimab reduced viral load from baseline through to day 7, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline.[784] Casirivimab/imdevimab is not authorised for use in hospitalised patients or those who require oxygen as it has not shown benefit in these patients. Further enrollment of patients requiring high-flow oxygen or mechanical ventilation has been placed on hold due to a potential safety signal and an unfavourable risk/benefit profile at this time. However, enrollment of hospitalised patients requiring either no or low-flow oxygen is being continued.[785] The UK RECOVERY trial is investigating whether adding casirivimab/imdevimab to usual standard of care (versus standard care alone) has any impact on all-cause 28-day mortality.[786] The National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against the use of casirivimab/imdevimab for the treatment of outpatients with mild to moderate COVID-19, and that it should not be considered the standard of care. Patients at higher risk for disease progression should be prioritised for treatment, and patients who are hospitalised should not receive casirivimab/imdevimab outside of a clinical trial.[3] The treatment must be administered as an intravenous infusion.

The FDA has issued an emergency-use authorisation for bamlanivimab (LY-CoV555) for the treatment of mild to moderate disease in children and adults. The authorisation covers patients with positive results of direct SARS-CoV-2 viral testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk for progressing to severe disease and/or hospitalisation. This includes patients who are 65 years of age or older, or who have certain chronic medical conditions.[787] Bamlanivimab, in combination with remdesivir, did not demonstrate efficacy among hospitalised patients who had COVID-19 without end-organ failure.[788] Another trial that was investigating the efficacy of bamlanivimab in hospitalised patients has been stopped based on trial data that suggests bamlanivimab is unlikely to help hospitalised patients recover from advanced disease. Other studies of bamlanivimab in recently diagnosed mild to moderate disease, recently diagnosed disease in the ambulatory setting, and prevention of disease in residents and staff at long-term care facilities remain ongoing.[789] The National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against the use of bamlanivimab for the treatment of outpatients with mild to moderate COVID-19, and that it should not be considered the standard of care. Patients at higher risk for disease progression should be prioritised for treatment, and patients who are hospitalised should not receive bamlanivimab outside of a clinical trial.[3] The Infectious Diseases Society of America recommends against the routine use of bamlanivimab in ambulatory patients; however, it states that bamlanivimab may be a reasonable treatment option in patients at increased risk.[601]

The combination AZD7442 (AZD8895 and AZD1061) is currently in phase 2 trials and is set to advance to phase 3 trials. This combination of long-acting antibodies derived from convalescent patients has been engineered to extend the half-life of the antibodies and increase protection to 6 to 12 months after administration.[790]

Convalescent plasma

Clinical trials to determine the safety and efficacy of convalescent plasma that contains antibodies to SARS-CoV-2 in patients with COVID-19 are ongoing. In the US, the FDA has issued an emergency-use authorisation for convalescent plasma for the treatment of COVID-19 in hospitalised patients.[791] This follows publication of a preprint (not peer reviewed) of an open-label, multicentre, expanded access programme study of over 35,000 patients that found convalescent plasma lowered 7-day mortality by 9% in hospitalised patients when given within 3 days of diagnosis, and by 12% when given 4 or more days later.[792]

A meta-analysis and systematic review with a total of 5444 patients found that the use of convalescent plasma reduced mortality, increased viral clearance, and resulted in clinical improvement in patients with COVID-19; however, the evidence is of low quality and further randomised controlled trials are required.[793] An open-label, randomised controlled trial in hospitalised patients with moderate disease found that convalescent plasma was not associated with a reduction in progression to severe disease or all-cause mortality.[794] However, a randomised, double-blind, placebo-controlled trial in older patients with mild disease who received convalescent plasma within 72 hours after the onset of symptoms found that early administration reduced the progression to severe disease.[795]

The authors of a Cochrane review were uncertain as to whether convalescent plasma is beneficial for hospitalised patients with COVID-19. The currently available evidence on the safety and efficacy of convalescent plasma for the treatment of hospitalised patients is of low or very low certainty.[796]

Anti-SARS-CoV-2 antibody levels in the plasma appear to affect outcome. Transfusion of plasma with higher anti–SARS-CoV-2 immunoglobulin G antibody levels was associated with a lower risk of death compared with transfusion of plasma with lower antibody levels in one retrospective study based on an US national registry.[797]

The National Institutes of Health guidelines panel says that there is currently insufficient evidence to recommend either for or against the use of convalescent plasma for the treatment of COVID-19.[3] The Infectious Diseases Society of America recommends convalescent plasma only in the context of a clinical trial.[601] The UK RECOVERY trial is currently investigating whether convalescent plasma is effective in the treatment of COVID-19.

Baricitinib

Baricitinib, an oral Janus kinase inhibitor, may prevent the dysregulated production of proinflammatory cytokines observed in patients with severe/critical COVID-19. The FDA has issued an emergency-use authorisation for baricitinib in combination with remdesivir for the treatment of suspected or confirmed COVID-19 in hospitalised adults and children aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.[798] The authorisation is based on a randomised, double-blind, placebo-controlled trial that found baricitinib plus remdesivir was shown to reduce time to recovery (defined as either being discharged from the hospital, or being hospitalised 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.[799] The National Institutes of Health guidelines panel states that there are insufficient data to recommend either for or against the use of baricitinib in combination with remdesivir for the treatment of hospitalised patients in cases where corticosteroids can be used instead. In rare cases where corticosteroids cannot be used, the panel recommends baricitinib in combination with remdesivir for the treatment of hospitalised, non-intubated patients who require oxygen supplementation. The panel recommends against the use of baricitinib without remdesivir. There is insufficient data to recommend either for or against the use of baricitinib in combination with corticosteroids.[3]

Ivermectin

Ivermectin, a broad-spectrum antiparasitic agent, has been shown to be effective against SARS-CoV-2 in vitro.[800] Numerous registered clinical studies of ivermectin, either alone or in combination with other drugs (e.g., doxycycline), are ongoing in many countries for the treatment or prevention of COVID-19. A systematic review and meta-analysis found that adding ivermectin to usual care led to significant clinical improvement and a significant reduction in all-cause mortality compared with usual care; however, the quality of evidence was very low.[801] The results of several randomised trials and retrospective cohort studies have been published or made available as preliminary reports (not peer reviewed as yet). Some studies showed no benefits or worsening of disease after ivermectin use; others reported a shorter time to symptom resolution, shorter time to viral clearance, greater reduction in inflammatory markers, and lower mortality rates in patients who received ivermectin compared with patients who received a comparator drug or placebo. The National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of ivermectin for the treatment of COVID-19, and that results from adequately powered, well-designed, and well-conducted clinical trials are needed.[3]

Hydroxychloroquine/chloroquine

Hydroxychloroquine and chloroquine are oral drugs that are indicated for the prophylaxis and treatment of malaria, as well as the treatment of some autoimmune conditions. Both drugs show in vitro activity against SARS-CoV-2; however, hydroxychloroquine has been used more commonly in trials due to its better adverse-effect profile.[802][803]

Initial data from clinical trials of hydroxychloroquine seemed promising.[804][805][806] However, a living systematic review of current evidence (as of 21 September) concludes that there is low-strength evidence from trials and cohort studies that hydroxychloroquine has no positive effect on all-cause mortality or the need for mechanical ventilation. Trials show low strength of evidence for no positive effect on intubation or death and discharge from the hospital, whereas evidence from cohort studies about these outcomes remains insufficient. Data are insufficiently strong to support a treatment benefit of hydroxychloroquine for other outcomes (e.g., intensive care unit admission, symptom resolution). In trials where hydroxychloroquine is initiated in the outpatient setting, there is low strength of evidence that it reduces hospitalisation; however, there is insufficient evidence from cohort studies.[807][808] A preprint meta-analysis found that early use of hydroxychloroquine in non-hospitalised patients reduced the risk of infection, hospitalisation, and death (grouped together into a composite outcome – a limitation of the study) by 24%, with no serious adverse cardiac events reported.[809] A systematic review of 43 mainly retrospective or prospective observational preprint studies also found it is effective when used early in the outpatient setting.[810]

Hydroxychloroquine is in trials for the prevention of COVID-19 (mainly in healthcare workers). A randomised, double-blind, placebo-controlled trial with 132 healthcare workers found that there was no significant difference in infection rates in participants receiving daily hydroxychloroquine for 8 weeks compared with placebo, and mild adverse effects were more common in the hydroxychloroquine arm. However, this trial was terminated early and may have been underpowered to detect a clinically important difference.[811] Post-exposure prophylaxis with hydroxychloroquine has not been shown to be effective in other trials.[812][813]

The WHO and the National Institutes of Health have prematurely discontinued their clinical trials of hydroxychloroquine citing a lack of efficacy. The WHO Solidarity trial found that hydroxychloroquine appears to have little or no effect on hospitalised patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[763] Results from the UK RECOVERY trial found that hydroxychloroquine does not reduce the risk of death at 28 days compared with usual care.[814] The WHO strongly recommends against the use of hydroxychloroquine or chloroquine, regardless of disease severity, based on low- to moderate-certainty evidence.[553][597]

The National Institutes of Health guidelines panel recommends against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 in hospitalised patients. The panel recommends against the use of both drugs in non-hospitalised patients except in the context of a clinical trial.[3] The Infectious Diseases Society of America strongly recommends against the use of hydroxychloroquine or chloroquine (with or without azithromycin) for the treatment of COVID-19 in hospitalised patients based on moderate-quality evidence.[601]

The FDA has revoked its emergency-use authorisation for hydroxychloroquine and chloroquine as it believes the potential benefits no longer outweigh the known and potential risks.[588]

If used, hydroxychloroquine and chloroquine should be used with caution in patients with pre-existing cardiovascular disease due to the risk of arrhythmias, and a baseline echocardiogram is recommended before treatment, particularly in patients who are critically ill.[815][816] Caution is recommended when using these drugs with other drugs that prolong the QT interval (e.g., azithromycin) due to an increased risk of QT interval prolongation and/or ventricular tachycardia (including Torsades de Pointes).[817][818][819]

A phase 1 trial of inhaled liposomal hydroxychloroquine has been approved.[820]

Lopinavir/ritonavir

An oral antiretroviral protease inhibitor currently approved for the treatment of HIV infection.

Results from the UK RECOVERY trial found that there is no beneficial effect of lopinavir/ritonavir in hospitalised patients with COVID-19. There was no significant difference in 28-day mortality, risk of progression to mechanical ventilation or death, or duration of hospital stay between the two treatment arms (lopinavir/ritonavir versus usual care alone).[821]

The WHO Solidarity trial found that lopinavir/ritonavir appears to have little or no effect on hospitalised patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[763] A systematic review and meta-analysis found that lopinavir/ritonavir had no significant advantage in efficacy over standard care, no antivirals, or other antiviral treatments.[822] The WHO strongly recommends against the use of lopinavir/ritonavir, regardless of disease severity, based on low- to moderate-certainty evidence.[553][597]

The National Institutes of Health guidelines panel recommends against the use of lopinavir/ritonavir for the treatment of COVID-19 except in the context of a clinical trial.[3] The Infectious Diseases Society of America recommends against the use of lopinavir/ritonavir based on moderate-certainty evidence.[601]

Lopinavir/ritonavir causes QT interval prolongation and may increase the risk of bradycardia, especially in older, critically ill patients.[823]

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) is being trialled in some patients with COVID-19.[47][824] A retrospective study of 58 patients with severe COVID-19 found that IVIG, when used as an adjuvant treatment within 48 hours of admission, may reduce the use of mechanical ventilation, reduce hospital/intensive care unit stay, and reduce 28-day mortality; however, this study had several limitations.[825] There is currently insufficient evidence to recommend IVIG for the treatment of COVID-19.[826] The National Institutes of Health guidelines panel recommends against the use of non-SARS-CoV-2-specific IVIG for the treatment of COVID-19 except in the context of a clinical trial.[3]

Anakinra

Anakinra, an interleukin-1 inhibitor, is being trialled in COVID-19 patients for the treatment of virus-induced cytokine release syndrome. It is already approved in some countries for other indications. Addition of high-dose intravenous anakinra to non-invasive ventilation and standard care (which included hydroxychloroquine and lopinavir/ritonavir) in COVID-19 patients with moderate to severe acute respiratory distress syndrome and hyperinflammation was associated with a higher survival rate at 21 days in a small retrospective study.[827] A small prospective cohort study found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality in patients with severe disease.[828] A small retrospective case series found that anakinra could be beneficial in patients with cytokine release syndrome when initiated early after the onset of acute hypoxic respiratory failure.[829] A phase 3 trial comparing anakinra with optimised standard of care in hospitalised patients has been suspended due to excess mortality in the intervention arm.[830]

The National Institutes of Health guidelines panel states that there is currently insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19.[3] The National Institute for Health and Care Excellence in the UK states that there is no evidence available to determine whether anakinra is effective, safe, or cost-effective for treating adults and children with secondary haemophagocytic lymphohistiocytosis triggered by SARS-CoV-2 or a similar coronavirus.[831]

Antigranulocyte–macrophage colony-stimulating factor (GM-CSF) monoclonal antibodies

Mavrilimumab was associated with improved clinical outcomes compared with standard care in non-mechanically ventilated patients with severe disease and systemic hyperinflammation in a single-centre prospective cohort study.[832] Lenzilumab was associated with a reduction in the relative risk of progression to invasive mechanical ventilation and/or death in high-risk COVID-19 patients with severe pneumonia compared with a matched control cohort of patients who received standard care alone in a small study of 39 patients.[833][834]

Tumour necrosis factor (TNF)-alpha inhibitors

A trial has been launched in the UK to investigate whether adalimumab is effective for treating patients in the community, including care homes. The trial will test two dose levels of adalimumab, and patients will be followed up for 4 months. The trial comes after a recent study reported that TNF inhibitors were associated with a decreased odds of hospitalisation in people with rheumatic disease and COVID-19.[835]

Stem cell therapy

Stem cell therapy is being investigated to treat patients with COVID-19 in clinical trials. It is thought that mesenchymal stem cells can reduce the pathological changes that occur in the lungs, and inhibit the cell-mediated immune inflammatory response.[836] 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 COVID-19 patients; however, an interim analysis of data found that the trial is not likely to meet its 30-day mortality reduction end point and has stopped enrolment, although the trial will be completed with the patients currently enrolled, with follow-up as planned.[837] The National Institutes of Health guidelines panel recommends against the use of mesenchymal stem cells for the treatment of COVID-19 except in the context of a clinical trial.[3] Adipose-derived mesenchymal stem cells have been approved by the FDA for the treatment of severe COVID-19.

Granulocyte colony-stimulating factor (G-CSF)

Recombinant G-CSF plus usual care did not accelerate clinical improvement compared with usual care alone according to preliminary findings from a randomised clinical trial in patients with lymphopenia and no comorbidities. Larger studies are needed to determine whether G-CSF, which increases peripheral blood leukocyte and lymphocyte cell counts, is beneficial in COVID-19 patients.[838] Very low-certainty evidence suggests that recombinant G-CSF may reduce risk of death and need for mechanical ventilation compared with standard care.[598][599]

Bacille Calmette-Guerin (BCG) vaccine

The BCG vaccine is being trialled in some countries for the prevention of COVID-19, including in healthcare workers. There is some evidence that BCG vaccination prevents other respiratory tract infections in children and older people mediated by induction of innate immune memory.[839] However, there is no evidence to support its use in COVID-19, and the WHO does not recommend it for the prevention of COVID-19.[840]

Bemcentinib

An experimental small molecule that inhibits AXL kinase. Bemcentinib has previously demonstrated a role in the treatment of cancer, but has also been reported to have antiviral activity in preclinical models, including activity against SARS-CoV-2. It was the first candidate to be selected as part of the UK’s Accelerating COVID-19 Research and Development (ACCORD) study.[841] The study has stopped recruiting new patients into the trial due to the reduction of new COVID-19 cases in the UK. Patients already recruited will continue on treatment as per the study protocol.

Angiotensin-II receptor antagonists

Angiotensin-II receptor antagonists such as losartan are being investigated as a potential treatment because it is thought that the angiotensin-converting enzyme-2 (ACE2) receptor is the main binding site for the virus.[842][843][844] However, some experts believe that these drugs may worsen COVID-19 due to overexpression of ACE2 in people taking these drugs.

Angiotensin-II receptor agonists

C21, a first-in-class oral low molecular weight angiotensin-II receptor agonist, demonstrated efficacy in a randomised, double-blind, placebo-controlled phase 2 trial. C21 reduced the risk of needing oxygen or mechanical ventilation in hospitalised patients compared with placebo.[845][846]

Interferons

A randomised, placebo-controlled, phase 2 study found that nebulised interferon beta-1a was associated with a higher odds of clinical improvement and more rapid recovery.[847] The WHO Solidarity trial found that interferon beta-1a appears to have little or no effect on hospitalised patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[763] Triple therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin has been tested in hospitalised COVID-19 patients in a small open-label randomised phase 2 trial. Patients who received triple therapy had a significantly shorter median time to a negative nasopharyngeal swab result compared with the control group (lopinavir/ritonavir only). Patients had mild to moderate disease at the time of enrollment.[848] 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.[849][850] Clinical trials of inhaled remdesivir, and remdesivir plus interferon beta-1a, have started.[851] The National Institutes of Health guidelines panel recommends against the use of interferons for the treatment of severe or critically ill patients, except in the context of a clinical trial.[3]

Antibiotics

The PRINCIPLE trial in the UK is currently evaluating three treatment strategies in older people (people aged over 65 years, or people aged over 50 years with an underlying health condition): usual care alone; usual care plus azithromycin; and usual care plus doxycycline.[852] 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 hospitalised patients compared with usual standard care alone. The UK Medicines and Healthcare products Regulatory Agency recommends that azithromycin should not be used in the management of confirmed or suspected COVID-19 in hospitalised patients unless there are additional indications for which its use remains appropriate.[853]

Brilacidin

An investigational drug that belongs to a new class of antibiotics called host defense protein mimetics. Brilacidin has antibacterial, antiviral, and anti-inflammatory properties, and exhibits potent in vitro activity against SARS-CoV-2.[854] The FDA has granted fast-track designation to the drug, and a phase 2 trial is due to start soon.[855]

Favipiravir

A meta-analysis found that there was significant clinical and radiological improvement following treatment with favipiravir compared with standard of care.[856]

Colchicine

Colchicine, an anti-inflammatory agent that is used for the management of gout and other inflammatory conditions, is being tested in various clinical trials. The UK RECOVERY trial is currently investigating whether colchicine is effective in the treatment of COVID-19. The main outcome the trial will assess is mortality after 28 days. Other outcomes include the impact on hospital stay and the need for ventilation.[857]

Aspirin

Although it is not currently recommended, aspirin may be effective for the prevention of blood clots in patients with COVID-19. The UK RECOVERY trial is currently investigating whether aspirin plus usual standard of care reduces mortality at 28 days, length of hospital stay, or the need for ventilation in hospitalised patients with COVID-19 compared with standard of care alone.[858]

Vitamin C

Vitamin C supplementation has shown promise in the treatment of viral infections.[859] High-dose intravenous vitamin C is being trialled in some centres for the treatment of severe COVID-19.[860] There is no evidence to support or refute the use of vitamin C in the treatment of patients with COVID-19; however, a substantial number of trials are ongoing.[861] A pilot randomised controlled trial found high-dose intravenous vitamin C may show potential benefit in improving oxygenation and reducing mortality in critically ill patients; however, the trial was underpowered.[862] The National Institutes of Health guidelines panel states that there is insufficient data to recommend either for or against vitamin C for the treatment of COVID-19 in non-critically ill or critically ill patients.[3]

Vitamin D

Vitamin D supplementation has been associated with a reduced risk of acute respiratory infections such as influenza.[863][864][865][866] Vitamin D is being trialled in patients with COVID-19.[867][868] However, there is no evidence to recommend vitamin D for the prophylaxis or treatment of COVID-19 as yet.[869] A pilot randomised controlled trial found that high-dose calcifediol, a vitamin D3 analogue, significantly reduced the need for intensive care unit treatment in hospitalised patients, and may improve clinical outcomes.[870] 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.[871] The National Institutes of Health guidelines panel states that there is insufficient data to recommend either for or against vitamin D.[3]

Probiotics

There is emerging evidence that gut dysbiosis may have a role in the pathogenesis of COVID-19.[296][297][298] Probiotics may represent a complementary approach for the prevention or treatment of mucosal damage or inflammation through the modulation of gut microbiota; however, further research is required.[872]

Traditional Chinese medicine

Traditional Chinese medicine is being used in patients with COVID-19 in China according to local guidelines and as part of clinical trials.[873] A meta-analysis found that Chinese medicine combined with conventional treatment significantly improved clinical efficacy compared with conventional treatment alone; however, high-quality, multiple-centre, large-sample randomised controlled trials are needed.[874]

Fluvoxamine

A selective serotonin-reuptake inhibitor with a strong affinity for the sigma-1 receptor. Sigma-1 agonism is a potential mechanism for immune modulation. Previous studies have shown that fluvoxamine reduces the damaging aspects of the inflammatory response during sepsis. A double-blind, randomised, preliminary trial of fluvoxamine versus placebo in adult outpatients with symptomatic COVID-19 found that patients treated with fluvoxamine had a lower likelihood of deterioration over 15 days. However, the study was limited by sample size and short follow-up duration.[875]

Hyperbaric oxygen

Preliminary evidence suggests that hyperbaric oxygen treatment has been successfully used to treat deteriorating, severely hypoxaemic patients with severe COVID-19.[876][877] Clinical trials are currently recruiting.[878][879]

Nitric oxide

Studies indicate that nitric oxide may help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication in epithelial cells.[880] The FDA has approved an investigational drug application for inhaled nitric oxide to be studied in a phase 3 study of up to 500 patients with COVID-19. Other studies are currently recruiting.

Aviptadil

A synthetic form of vasoactive intestinal peptide (also known as RLF-100) has been granted an expanded access protocol (which makes the treatment available to patients who have exhausted approved therapies and who are not eligible for the current clinical trial of aviptadil) and fast-track designation by the FDA for the treatment of respiratory failure in patients with COVID-19. Intravenous and inhaled formulations are currently in phase 2 and 3 clinical trials in the US.[881][882] The manufacturer has requested emergency-use authorisation from the FDA for the treatment of patients with critical disease and respiratory failure who have exhausted approved therapies, based on the results of a small case-control study.[883]

Icatibant

A selective bradykinin B2 receptor antagonist. A small exploratory case-control study of 9 people found an association between the administration of icatibant and improved oxygenation, suggesting that administration in the early stages of disease when patients are hypoxic may be beneficial. Treatment strategies that target the kallikrein-kinin system require further investigation in randomised trials for patients with COVID-19.[884]

Tradipitant

A neurokinin 1 antagonist that is being trialled for the treatment of neurogenic inflammation of the lung secondary to SARS-CoV-2 infection. Interim analysis of the ODYSSEY study found that hospitalised patients improved sooner when treated with tradipitant compared with placebo. The trial is ongoing.[885][886]

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