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 No treatments have been approved or shown to be safe and effective for the treatment of COVID-19, with the exception of remdesivir, which has been granted an emergency-use authorization in the US. There are several treatments being used off-label (use of a licensed medication for an indication that has not been approved by a national drug regulatory authority), on a compassionate-use basis, or as part of a randomized controlled trial.[583][584] 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. For example, chloroquine/hydroxychloroquine, azithromycin, oseltamivir, and lopinavir/ritonavir can all prolong the QT interval and are all potentially associated with an increased risk of cardiac death.[585] Drug-drug interactions with the patient’s existing medication(s) must also be considered (e.g., antivirals can interact with many drugs including direct oral anticoagulants). The World Health Organization (WHO) and its partners have launched the Solidarity trial, a large international study to compare four different treatments (local standard of care plus remdesivir, lopinavir/ritonavir, lopinavir/ritonavir plus interferon beta, or hydroxychloroquine/chloroquine) compared with local standard of care alone (which may include other experimental drug therapies as part of local standard of care).[586] A national trial to identify treatments that may be beneficial for people hospitalized with suspected or confirmed COVID-19 is ongoing in the UK. The randomized evaluation of COVID-19 therapy (RECOVERY) trial is testing the following therapeutic options: lopinavir/ritonavir; low-dose dexamethasone; hydroxychloroquine; azithromycin; tociluzumab; and convalescent plasma. RECOVERY trial external link opens in a new window

Remdesivir

A novel, investigational, intravenous nucleoside analog 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 has issued an emergency-use authorization for remdesivir for the treatment of suspected or confirmed COVID-19 in adults and children with hospitalized severe disease (defined as patients with low blood oxygen levels or needing oxygen therapy or more intensive breathing support such as a mechanical ventilator).[587] This authorization is based on preliminary results from a randomized, placebo-controlled trial of remdesivir in 1063 patients hospitalized 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 hospitalization, or hospitalization 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.[588] The National Institutes of Health guidelines recommend prioritizing remdesivir in hospitalized patients with COVID-19 who require supplemental oxygen, but who are not on high-flow oxygen, noninvasive 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 mild or moderate COVID-19, or patients with more severe disease who require high-flow oxygen, noninvasive 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 hospitalized patients with severe COVID-19, with the same treatment duration as recommended above.[537] A 5-day course was found to be as safe and efficacious as a 10-day course in patients with severe disease not requiring ventilation; however, this was not a placebo-controlled trial.[589] Preliminary results from an open-label phase 3 trial in patients with moderate disease found that a 5-day course resulted in greater clinical improvement at day 11 compared with standard of care; however, full results are yet to be published.[590] Early results from one trial of patients treated with remdesivir on a compassionate-use basis indicated that approximately two-thirds of patients showed signs of clinical improvement (68% of patients had an improvement in oxygen support requirements); however, the study had no control arm and the majority of patients reported adverse effects.[591] A randomized, placebo-controlled trial in 240 hospitalized patients with severe COVID-19 in China found that remdesivir was not associated with significantly clinical benefits; however, the trial was underpowered, and while it showed some nonsignificant trends for benefit, it did not meet its primary end point.[592] 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 with mild, moderate, or severe COVID-19 who are on oxygen therapy. However, no statistically significant differences were found for mortality and serious adverse events.[593] An expert guideline panel makes a weak recommendation for the use of remdesivir in severe disease, and supports more randomized trials as the quality of the evidence is low. BMJ: remdesivir for severe covid-19 – a clinical practice guideline external link opens in a new window Remdesivir appears to be safe to use in pregnancy.[594] 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.[595] The European Medicines Agency has recommended granting a conditional marketing authorization to remdesivir for the treatment of COVID-19 in adults and children 12 years of age and older with pneumonia who require supplemental oxygen.[596] 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.[597] A trial of inhaled remdesivir is about to start phase 1 clinical trials. 

Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine are oral drugs that have been used for the prophylaxis and treatment of malaria, and the treatment of certain autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus. Both drugs have in vitro activity against SARS-CoV-2, with hydroxychloroquine having relatively higher potency.[598][599] They are being trialed in patients for the treatment and prophylaxis of COVID-19. Initial data seemed promising, but evidence so far is weak and conflicting.[600] A small randomized controlled trial found that hydroxychloroquine (with or without azithromycin) was efficient in reducing viral nasopharyngeal carriage of SARS-CoV-2 in 3 to 6 days in most patients.[601] However, this trial has been criticized for its limitations, and results from a similar trial could not replicate these findings.[602][603] Another randomized trial in 62 patients in China found that hydroxychloroquine may shorten time to clinical recovery (in terms of resolution of fever and cough, and improvement of pneumonia on computed tomographic imaging); however, this study has not been peer reviewed as yet.[604] Early results from the largest randomized controlled trial completed so far of 150 people in China found that the overall 28-day negative conversion rate was not significantly different between patients who received hydroxychloroquine and those who received standard of care. However, addition of hydroxychloroquine led to more rapid normalization of C-reactive protein levels and recovery of baseline lymphopenia, which may be important. The time to the alleviation of symptoms was shorter compared with standard of care in the subgroup of patients who did not receive antiviral treatment in the post-hoc analysis. The rate of adverse effects was higher in the hydroxychloroquine group (diarrhea being the most common adverse effect). This study has not been peer reviewed yet and has several limitations (e.g., delay between symptom onset and starting treatment, inclusion of other antiviral therapies in the standard of care group).[605] According to an observational study of over 1400 hospitalized patients in New York, hydroxychloroquine was not associated with a reduced risk for intubation or death compared with those who did not receive hydroxychloroquine, and the authors conclude that further randomized controlled trials are needed.[606] Another observational study of 181 patients across four tertiary care centers in France found that in patients with severe COVID-19 who require oxygen, hydroxychloroquine appeared to have no effect on reducing admissions to intensive care or deaths at day 21 after hospital admission.[607] A multinational registry analysis of the use of hydroxychloroquine or chloroquine (with or without a macrolide antibiotic) found that the use of these regimens was independently associated with an increased risk of in-hospital mortality and ventricular arrhythmias; however, the study has now been retracted.[608] The study was criticized by more than 140 scientists and physicians in an open letter to the authors that lists numerous concerns about the validity of the study.[609][610] Preliminary results from the UK RECOVERY trial found that hydroxychloroquine does not reduce the risk of dying or improve other outcomes in hospitalized patients, and investigators have stopped enrolling participants into the hydroxychloroquine arm of the trial.[611] As a consequence of this, the WHO stopped the hydroxychloroquine arm of the Solidarity trial on 17 June.[612] A randomized, double-blind, placebo-controlled trial found that hydroxychloroquine did not prevent symptomatic infection when used as postexposure prophylaxis within 4 days of moderate- or high-risk exposure; however, the vast majority of participants were not able to access testing and the outcome was based on the presence of symptoms compatible with COVID-19 rather than a confirmed positive test result with molecular testing.[613] Despite these negative results, recently a multicenter retrospective observational study of over 2500 patients in the US found that treatment with hydroxychloroquine alone (and in combination with azithromycin) was associated with a reduction in mortality when controlling for risk factors.[614] A 5-day course of hydroxychloroquine did not substantially reduce symptom severity in outpatients with probable or confirmed early mild COVID-19 in a randomized, double-blind, placebo-controlled trial of nearly 500 people; however, only 58% of participants received SARS-CoV-2 testing.[615] An open-label randomized controlled trial of patients with mild to moderate disease found that a 7-day course of hydroxychloroquine (either with azithromycin or alone) did not result in better clinical outcomes as measured by a seven-level ordinal scale at 15 days compared with standard care, although the trial had several limitations.[616] Hydroxychloroquine has similar therapeutic effects to chloroquine, but fewer adverse effects, is considered safe in pregnancy, and is more readily available in some countries.[617] Both drugs must be used with caution in patients with preexisting cardiovascular disease due to the risk of arrhythmias.[618] It is reasonable to do a baseline echocardiogram before treatment whenever possible, particularly in patients who are critically ill.[619] Higher doses of chloroquine have been associated with an increased risk of QT interval prolongation compared with lower doses, especially when used in combination with other drugs that prolong the QT interval.[620] Because chloroquine/hydroxychloroquine and azithromycin can both cause QT interval prolongation, caution is recommended when using these drugs together.[621][622] The risk of QT interval prolongation and/or ventricular tachycardia (including Torsades de Pointes) is greater when these drugs are used in combination compared with the risk associated with either drug used alone (0.6% versus 1.5%).[623] A preprint study (not peer reviewed) found an increased risk of 30-day cardiovascular mortality when azithromycin was added to hydroxychloroquine in patients with COVID-19.[624] This combination is not recommended except in the context of a clinical trial.[3][537] Caution is recommended with the dosing regimen used for chloroquine due to the risk of chloroquine poisoning.[625] Guidelines in China and Italy recommend these drugs for the treatment of COVID-19; however, this is based on weak evidence.[626] Surviving Sepsis Campaign and National Institutes of Health guidelines concluded that there is insufficient evidence to offer any recommendation on use of these drugs in the intensive care unit.[512] The National Institutes of Health recommends against the use of either drug except in a clinical trial, but has stopped its clinical trials.[3] The Infectious Diseases Society of America recommends these drugs only in the context of a clinical trial.[537] The American Thoracic Society recommends that either drug may be used on a case-by-case basis provided the patient’s condition is severe enough to warrant investigational therapy, the benefits and risks of treatment are discussed with the patient, data is collected on outcomes, and the drug is not in short supply.[564] The European Medicines Agency (EMA) has stressed that these drugs have not been shown to be effective in treating COVID-19 as yet, and should only be used in the context of clinical trials or emergency-use programs.[627] Based on results from the RECOVERY trial, the UK Medicines and Healthcare products Regulatory Agency has instructed researchers in the UK who are using hydroxychloroquine in clinical trials to suspend recruitment of further participants, although hydroxychloroquine will still be able to be used in trials for the prevention of COVID-19 in healthcare workers.[628] The FDA has revoked its emergency-use authorization for chloroquine and hydroxychloroquine as it believes the potential benefits no longer outweigh the known and potential risks.[629] It recommends that these drugs should not be used outside of the hospital setting or a clinical trial due to the risk of arrhythmias, especially when used in combination with azithromycin.[630] There is currently no strong evidence of efficacy of hydroxychloroquine or chloroquine in the treatment or prevention of COVID-19.[631] Centre for Evidence-Based Medicine: hydroxychloroquine for COVID-19 – what do the clinical trials tell us? external link opens in a new window

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.[632] A randomized controlled trial of 200 patients with severe disease found that treatment with lopinavir/ritonavir plus standard care (i.e., oxygen, noninvasive 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.[633] Preliminary results from the UK RECOVERY trial found that there is no beneficial effect of lopinavir/ritonavir in hospitalized 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.[634] Lopinavir/ritonavir may increase the risk of bradycardia, especially in older, critically ill patients.[635] Lopinavir/ritonavir should only be used 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 

Convalescent plasma

Convalescent plasma from patients who have recovered from viral infections has been used as a treatment in previous virus outbreaks including SARS, avian influenza, and Ebola virus infection.[636] 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. A randomized controlled trial found that convalescent plasma added to standard treatment did not significantly improve time to clinical improvement within 28 days in patients with severe or life-threatening disease. However, the trial was terminated early and may have been underpowered to detect a clinically important difference.[637] A systematic review of five studies found that convalescent plasma may reduce mortality in critically ill patients, have a beneficial effect on clinical symptoms, and reduce viral load.[638] The FDA is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of single patient emergency investigational new drug applications, and has issued guidance for its use. The FDA is encouraging patients who have recovered (complete resolution of symptoms for at least 2 weeks prior to donation; a negative reverse-transcription polymerase chain reaction [RT-PCR] test is not necessary to qualify for donation) to donate their plasma.[639][640][641] 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.[537] The authors of a Cochrane rapid review were uncertain as to whether convalescent plasma is beneficial for hospitalized 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. There is limited information regarding adverse effects and very low-certainty evidence for safety in patients with COVID-19.[642]

Intravenous immune globulin

Intravenous immune globulin (IVIG) is being trialed in some patients with COVID-19.[32][643] 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.[644] There is currently insufficient evidence to recommend IVIG for the treatment of COVID-19.[645] 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.[646] Recombinant, fully human monoclonal neutralizing 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.[647][648] Novel multi-antibody cocktail therapies (e.g., REGN-COV2) are also in clinical trials for prophylaxis or treatment.[649]

Interleukin-6 (IL-6) receptor antagonists

IL-6 receptor antagonist monoclonal antibodies (e.g., tocilizumab, sarilumab, siltuximab) are being trialed 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 retrospective cohort study found that clinical improvement and 28-day mortality were not statistically different between tocilizumab and standard of care.[650] Other studies found that the use of tocilizumab was associated with significantly shorter duration of vasopressor support, and that it may reduce the risk of noninvasive mechanical ventilation or death in patients with severe disease.[651][652] Tocilizumab was associated with a 45% lower mortality risk according to an observational study in a cohort of mechanically ventilated patients, despite being associated with a higher risk of superinfection (mainly due to ventilator-associated pneumonia). Patients with superinfection did not have a higher mortality rate compared with those without.[653] Trials of sarilumab have been halted in the US as the drug failed to reach primary and key secondary end points. 

Anakinra

Anakinra, an interleukin-1 inhibitor, is being trialed 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 noninvasive 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.[654] A small prospective cohort study found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality in patients with severe disease.[655] 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.[656] 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 hemophagocytic lymphohistiocytosis triggered by SARS-CoV-2 or a similar coronavirus.[657] 

Mavrilimumab

Mavrilimumab, an antigranulocyte–macrophage colony-stimulating factor receptor-alpha monoclonal antibody, was associated with improved clinical outcomes compared with standard care in nonmechanically ventilated patients with severe disease and systemic hyperinflammation in a single-center prospective cohort study.[658]

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.[659][660][661] 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 pathologic changes that occur in the lungs, and inhibit the cell-mediated immune inflammatory response.[662] 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.

Bacille Calmette-Guerin (BCG) vaccine

The BCG vaccine is being trialed 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.[663] 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.[664]

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.[665] 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.[666][667][668] 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 trialed in patients with COVID-19 (e.g., oseltamivir, darunavir, ganciclovir, favipiravir, baloxavir marboxil, umifenovir, ribavirin, interferon, leronlimab).[669][670][671][672][673][674][675][676][677][678] There is no evidence to support the use of umifenovir.[679] Triple therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin has been tested in hospitalized COVID-19 patients in a small open-label randomized 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 enrolment.[680] 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]

Vitamin C

Vitamin C supplementation has shown promise in the treatment of viral infections.[681] High-dose intravenous vitamin C is being trialed in some centers for the treatment of severe COVID-19.[682] 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.[683][684][685] Vitamin D is being trialed in patients with COVID-19.[686][687] However, there is no evidence to recommend vitamin D for the prophylaxis or treatment of COVID-19 as yet.[688] 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.[689] 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.[293][294][295] 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.[690]

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.[691]

Hyperbaric oxygen

Preliminary evidence suggests that hyperbaric oxygen treatment has been successfully used to treat deteriorating, severely hypoxemic patients with severe COVID-19.[692][693] Clinical trials are currently recruiting.[694][695]

Nitric oxide

Studies indicate that nitric oxide may help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication in epithelial cells.[696] 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.[697][698]

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