Emerging treatments

Introduction

Various treatments for COVID-19 are in clinical trials around the world. Global coronavirus COVID-19 clinical trial tracker external link opens in a new window There are several treatments being used off-label on a compassionate-use basis, or as part of a clinical trial. WHO: off-label use of medicines for COVID-19 external link opens in a new window 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).[694] 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.[695] International trials to identify treatments that may be beneficial, such as the World Health Organization’s (WHO) Solidarity trial and the UK’s randomised evaluation of COVID-19 therapy (RECOVERY) trial, are ongoing. WHO: “Solidarity” clinical trial for COVID-19 treatments external link opens in a new window RECOVERY trial external link opens in a new window

Remdesivir

A novel intravenous nucleoside analogue with broad antiviral activity that shows in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the US, the Food and Drug Administration (FDA) has issued an emergency-use authorisation for remdesivir for the treatment of suspected or confirmed COVID-19 in adults and children who are hospitalised, regardless of disease severity.[696] The authorisation is based on results from a randomised, placebo-controlled trial of remdesivir in 1063 patients hospitalised with severe COVID-19 run by the National Institute of Allergy and Infectious Disease (NIAID). The study found that patients taking a 10-day course of remdesivir had a faster time to recovery (i.e., defined as a patient no longer requiring hospitalisation, or hospitalisation no longer requiring oxygen or ongoing medical care) compared with placebo, with a median recovery time of 11 days versus 15 days. Results were significant only among patients who received oxygen. The mortality rate was 7.1% with remdesivir compared with 11.9% with placebo, although the difference was not statistically significant. The incidence of adverse effects was not significantly different between the two groups. Even though the trial was ongoing, the data and safety monitoring board made the recommendation to unblind the results to the trial team members from NIAID, who subsequently decided to make the results public.[697] The National Institutes of Health guidelines recommend prioritising remdesivir in hospitalised patients with COVID-19 who require supplemental oxygen, but who are not on high-flow oxygen, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation. The guidelines panel recommends that patients should receive treatment for 5 days or until hospital discharge, whichever comes first (patients who have not shown clinical improvement after 5 days can receive treatment for up to 10 days). The guidelines panel does not recommend for or against remdesivir for the treatment of patients with severe disease who require high-flow oxygen, non-invasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation, as there are insufficient data.[3] The Infectious Diseases Society of America recommends remdesivir over no antiviral treatment among hospitalised patients with severe COVID-19, with the same treatment duration as recommended above.[545] A UK National Institute for Health and Care Excellence review suggests there is some benefit with remdesivir compared with placebo for reducing supportive measures including mechanical ventilation and reducing time to recovery in patients who are on oxygen therapy. However, no statistically significant differences were found for mortality and serious adverse events.[698] An expert guideline panel makes a weak recommendation for the use of remdesivir in severe disease, and supports more randomised trials as the quality of the evidence is low. BMJ rapid recommendations: remdesivir for severe covid-19 – a clinical practice guideline external link opens in a new window A network meta-analysis found that both 5-day and 10-day remdesivir regimens were associated with higher odds of clinical improvement in hospitalised patients compared with placebo.[699] There are little data available to support the use of remdesivir in patients with mild or moderate disease. Hospitalised patients with moderate disease had a statistically significantly better clinical status after 5 days of treatment (but not 10 days of treatment) compared with those who received standard care at 11 days after initiation of treatment, but the difference was of uncertain clinical importance.[700] The National Institutes of Health guidelines panel does not recommend for or against remdesivir for the treatment of mild or moderate disease as there are insufficient data.[3] Remdesivir appears to be safe to use in pregnancy.[701] Possible adverse effects include elevated liver enzymes and infusion-related reactions (e.g., hypotension, nausea, vomiting, sweating, shivering). The FDA recommends against the concomitant use of remdesivir with chloroquine or hydroxychloroquine due to a drug interaction that may result in reduced antiviral activity of remdesivir, although this has not been observed in practice.[702] The European Medicines Agency has granted a conditional marketing authorisation to remdesivir for the treatment of COVID-19 in adults and children 12 years of age and older with pneumonia who require supplemental oxygen.[703] An interim clinical commissioning policy has been put in place to define routine access to remdesivir in the treatment of COVID-19 across the UK from 3 July.[704] Clinical trials of inhaled remdesivir, and remdesivir plus interferon beta-1a, have started.[705]

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 Food and Drug Administration has issued an emergency-use authorisation for convalescent plasma for the treatment of COVID-19 in hospitalised patients.[706] 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.[707] 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.[708] The authors of a Cochrane rapid review were uncertain as to whether convalescent plasma is beneficial for hospitalised patients with COVID-19. The completed studies were of poor quality, and the results could be related to natural progression of the disease or to other treatments the patient receives. The currently available evidence on the safety and efficacy of convalescent plasma for the treatment of hospitalised patients is of very low certainty.[709] 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.[545] 

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.[710][711] Initial data from clinical trials of hydroxychloroquine seemed promising.[712][713][714] However, a living systematic review of current evidence (as of 27 August) 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.[715][716] A meta-analysis of randomised controlled trials found that hydroxychloroquine showed no benefit in the treatment of mild to moderate disease also.[717] The WHO and the National Institutes of Health have prematurely discontinued their clinical trials of hydroxychloroquine citing a lack of efficacy; however, results are yet to be published. Preliminary results from the UK RECOVERY trial found that hydroxychloroquine does not reduce the risk of dying or improve other outcomes in hospitalised patients, and investigators have stopped enrolling participants into the hydroxychloroquine arm of the trial.[718] The National Institutes of Health guideline 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.[545] 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.[539] 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.[719][720] 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).[721][722][723] 

Lopinavir/ritonavir

An oral antiretroviral protease inhibitor currently approved for the treatment of HIV Infection. Lopinavir/ritonavir has been used in clinical trials for the treatment of COVID-19. Results from one small case series found that evidence of clinical benefit with lopinavir/ritonavir was equivocal.[724] A randomised controlled trial of 200 patients with severe disease found that treatment with lopinavir/ritonavir plus standard care (i.e., oxygen, non-invasive and invasive ventilation, antibiotics, vasopressors, renal replacement therapy, and extracorporeal membrane oxygenation, as necessary) was not associated with an decreased time to clinical improvement compared with standard care alone, and 28-day mortality was similar in both groups.[725] Preliminary 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 duration of hospital stay between the two treatment arms (lopinavir/ritonavir versus usual care alone), and the results were consistent in different subgroups of patients.[726] Interim data from the WHO Solidarity trial found that lopinavir/ritonavir has little or no reduction in the mortality of hospitalised COVID-19 patients when compared with standard of care.[727] Lopinavir/ritonavir causes QT interval prolongation and may increase the risk of bradycardia, especially in older, critically ill patients.[728] 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] Centre for Evidence-Based Medicine: lopinavir/ritonavir – a rapid review of effectiveness in COVID-19 external link opens in a new window

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) is being trialled in some patients with COVID-19.[32][729] 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.[730] There is currently insufficient evidence to recommend IVIG for the treatment of COVID-19.[731] 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]

Monoclonal antibody treatments

SARS-CoV-2 monoclonal antibodies have the potential to be used for prophylaxis and treatment of COVID-19.[732] Recombinant, fully human monoclonal neutralising antibodies, such as JS016 and LY-COV555, are in development. 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. Both antibody treatments have started phase 1 studies.[733][734] Novel multi-antibody cocktail therapies (e.g., REGN-COV2) are also in clinical trials for prophylaxis or treatment.[735] The UK RECOVERY trial is investigating whether adding REGN-COV2 to usual standard of care (versus standard care alone) has any impact on all-cause 28-day mortality.[736]

Interleukin-6 (IL-6) inhibitors

IL-6 inhibitors (e.g., tocilizumab, siltuximab) are being trialled in COVID-19 patients for the treatment of virus-induced cytokine release syndrome. These drugs are already approved in some countries for other indications. A meta-analysis of 23 observational studies found that tocilizumab plus standard of care may reduce mortality and the need for mechanical ventilation in patients with severe disease.[737] However, the randomised controlled COVACTA trial failed to meet its primary end point of clinical status, and found that tocilizumab did not improve mortality. Full results are yet to be published.[738] 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]

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.[739] A small prospective cohort study found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality in patients with severe disease.[740] 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.[741] 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.[742]

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.[743] 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.[744][745]

Janus kinase inhibitors

Janus kinase inhibitors (e.g., fedratinib, ruxolitinib, baricitinib) are currently in clinical trials for the treatment of COVID-19-associated cytokine release syndrome.[746][747][748] The National Institutes of Health guidelines panel recommends against the use of Janus kinase inhibitors for the treatment of COVID-19 except in the context of a clinical trial.[3]

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.[749] 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.[750]

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.[751] 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.[752]

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.[753] 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.[754][755][756] However, some experts believe that these drugs may worsen COVID-19 due to overexpression of ACE2 in people taking these drugs. 

Other antivirals

Various other antiviral drugs (monotherapy and combination therapy) are being trialled in patients with COVID-19 (e.g., oseltamivir, darunavir, ganciclovir, favipiravir, baloxavir marboxil, umifenovir, ribavirin, interferon, leronlimab).[757][758][759][760][761][762][763][764][765][766] There is no evidence to support the use of umifenovir.[767] 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.[768] 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.[769]

Ivermectin

Ivermectin, a broad-spectrum antiparasitic agent, has been shown to be effective against SARS-CoV-2 in vitro.[770] It is unclear whether the doses necessary to achieve antiviral activity against SARS-CoV-2 are attainable in humans.[771] Numerous registered clinical studies of ivermectin, either alone or in combination with other drugs (e.g., doxycycline, hydroxychloroquine), are ongoing in many countries for the treatment or prevention of COVID-19. Further research in randomised controlled trials is necessary. The National Institutes of Health guidelines panel recommends against the use of ivermectin for the treatment of COVID-19 except in the context of a clinical trial.[3]

Vitamin C

Vitamin C supplementation has shown promise in the treatment of viral infections.[772] High-dose intravenous vitamin C is being trialled in some centres for the treatment of severe COVID-19.[773] 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.[774] The National Institutes of Health guidelines panel states that there is insufficient data to recommend either for or against vitamin C.[3]

Vitamin D

Vitamin D supplementation has been associated with a reduced risk of respiratory infections such as influenza in some studies.[775][776][777] Vitamin D is being trialled in patients with COVID-19.[778][779] However, there is no evidence to recommend vitamin D for the prophylaxis or treatment of COVID-19 as yet.[780] 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.[781] The UK National Institute for Health and Care Excellence states that while there is no evidence to support taking vitamin D specifically to prevent or treat COVID-19, it does recommend that all people should take a vitamin D supplement daily as per UK government advice to maintain bone and muscle health during the pandemic, especially if they are not getting enough sun exposure due to shielding or self-isolating.[782] 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.[315][316][317] 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.[783]

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.[784]

Hyperbaric oxygen

Preliminary evidence suggests that hyperbaric oxygen treatment has been successfully used to treat deteriorating, severely hypoxaemic patients with severe COVID-19.[785][786] Clinical trials are currently recruiting.[787][788]

Nitric oxide

Studies indicate that nitric oxide may help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication in epithelial cells.[789] 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) 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.[790][791]

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.[792]

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.[793][794]

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