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).[628] 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.[629] International trials to identify treatments that may be beneficial, such as the World Health Organization’s (WHO) Solidarity trial (the world’s largest randomized controlled trial on COVID-19 therapeutics across 30 countries), and the UK’s randomized 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

Convalescent plasma

Clinical trials to determine the safety and efficacy of convalescent plasma that contains antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with COVID-19 are ongoing. In the US, the Food and Drug Administration has issued an emergency-use authorization for convalescent plasma for the treatment of COVID-19 in hospitalized patients.[630] This follows publication of a preprint (not peer reviewed) of an open-label, multicenter, expanded access program study of over 35,000 patients that found convalescent plasma lowered 7-day mortality by 9% in hospitalized patients when given within 3 days of diagnosis, and by 12% when given 4 or more days later.[631] 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 randomized controlled trials are required.[632] The authors of a Cochrane review were uncertain as to whether convalescent plasma is beneficial for hospitalized patients with COVID-19. The currently available evidence on the safety and efficacy of convalescent plasma for the treatment of hospitalized patients is of low or very low certainty.[633] 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.[532] 

Monoclonal antibody treatments

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.[634] Multi-antibody cocktail therapies are currently in clinical trials. REGN-COV2 (a combination of REGN10933 plus RGN10987) is in phase 3 clinical trials.[635] 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.[636] REGN-COV2 is currently only recommended in the context of a clinical trial.[637] The manufacturer has submitted a request to the Food and Drug Administration (FDA) for emergency-use authorization. Trial data is yet to be published. The combination of LY-CoV016 and LY-CoV555 (bamlanivimab) is currently undergoing a randomized, placebo-controlled phase 2 trial in patients with mild to moderate disease.[638] Interim results showed that the combination reduced viral load at day 11, symptoms, and hospitalizations. The manufacturer has submitted a request to the FDA for emergency-use authorization of LY-CoV555 for monotherapy in higher-risk patients who have been recently diagnosed with mild to moderate disease, and expects to submit an application for combination therapy soon. However, the phase 3 trial has been put on hold for safety reasons as it reached a predefined boundary for safety at day 5 of treatment. No further details are available as yet.[639] Trial data is yet to be published.[640] 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.[641]

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.[642][643] Initial data from clinical trials of hydroxychloroquine seemed promising.[644][645][646] 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 hospitalization; however, there is insufficient evidence from cohort studies.[647][648] A preprint meta-analysis found that early use of hydroxychloroquine in nonhospitalized patients reduced the risk of infection, hospitalization, and death (grouped together into a composite outcome – a limitation of the study) by 24%, with no serious adverse cardiac events reported.[649] A systematic review of 43 mainly retrospective or prospective observational preprint studies also found it is effective when used early in the outpatient setting.[650] Hydroxychloroquine is in trials for the prevention of COVID-19 (mainly in healthcare workers). A randomized, 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.[651] The WHO and the National Institutes of Health have prematurely discontinued their clinical trials of hydroxychloroquine citing a lack of efficacy. Interim results from the WHO Solidarity trial found that hydroxychloroquine appears to have little or no effect on 28-day mortality or the in-hospital course among hospitalized patients.[555] Results from the UK RECOVERY trial found that hydroxychloroquine does not reduce the risk of death at 28 days compared with usual care.[652] The National Institutes of Health guidelines panel recommends against the use of hydroxychloroquine or chloroquine for the treatment of COVID-19 in hospitalized patients. The panel recommends against the use of both drugs in nonhospitalized 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 hospitalized patients based on moderate-quality evidence.[532] The FDA has revoked its emergency-use authorization for hydroxychloroquine and chloroquine as it believes the potential benefits no longer outweigh the known and potential risks.[571] If used, hydroxychloroquine and chloroquine should be used with caution in patients with preexisting cardiovascular disease due to the risk of arrhythmias, and a baseline echocardiogram is recommended before treatment, particularly in patients who are critically ill.[653][654] 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).[655][656][657] A phase 1 trial of inhaled liposomal hydroxychloroquine has been approved.[658]

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.[659] 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.[660] 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 death, or duration of hospital stay between the two treatment arms (lopinavir/ritonavir versus usual care alone).[661] Interim results from the WHO Solidarity trial found that lopinavir/ritonavir appears to have little or no effect on 28-day mortality or the in-hospital course among hospitalized patients.[555] However, lopinavir/ritonavir may reduce time to symptom resolution.[531] Lopinavir/ritonavir causes QT interval prolongation and may increase the risk of bradycardia, especially in older, critically ill patients.[662] 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 immune globulin

Intravenous immune globulin (IVIG) is being trialed in some patients with COVID-19.[34][663] 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.[664] There is currently insufficient evidence to recommend IVIG for the treatment of COVID-19.[665] 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]

Interleukin-6 (IL-6) inhibitors

IL-6 inhibitors (e.g., tocilizumab, 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 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.[666] The randomized controlled phase 3 EMPACTA trial found that tocilizumab reduced the need for mechanical ventilation in hospitalized patients compared with placebo, although there was no statistical difference in mortality between the two arms.[667] However, the randomized controlled phase 3 COVACTA trial failed to meet its primary end point of clinical status, and found that tocilizumab did not improve mortality.[668] Full results of both trials are yet to be published. Other randomized trials also give conflicting results.[669][670][671][672] 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 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.[673] A small prospective cohort study found that anakinra significantly reduced the need for invasive mechanical ventilation and mortality in patients with severe disease.[674] 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.[675] 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.[676] 

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

Mavrilimumab 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.[677] 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.[678][679]

Tumor 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 hospitalization in people with rheumatic disease and COVID-19.[680]

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.[681][682][683] Initial data emerging from the Adaptive COVID-19 Treatment Trial indicates that baricitinib plus remdesivir reduces time to recovery in hospitalized patients compared with remdesivir alone.[684] 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.[685] 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 randomized 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.[686]

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.[687] 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.[688]

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.[689] 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.[690][691][692] However, some experts believe that these drugs may worsen COVID-19 due to overexpression of ACE2 in people taking these drugs. 

Other antivirals

Various antiviral drugs (monotherapy and combination therapy) are being trialed in patients with COVID-19. A meta-analysis found that there was significant clinical and radiologic improvement following treatment with favipiravir compared with standard of care.[693] There is no evidence to support the use of umifenovir.[694] 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.[695] Clinical trials of inhaled remdesivir, and remdesivir plus interferon beta-1a, have started.[696] A phase 2 trial found that peginterferon lambda reduced viral load and the number of participants with a negative nasopharyngeal swab at day 7 in outpatients with mild to moderate disease compared with placebo.[697][698] Interim results from the WHO’s Solidarity trial found that interferon beta-1a appears to have little or no effect on 28-day mortality or the in-hospital course among hospitalized patients.[555] 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 ages over 65 years, or people ages over 50 years with an underlying health condition): usual care alone; usual care plus azithromycin; and usual care plus doxycycline.[699]

Ivermectin

Ivermectin, a broad-spectrum antiparasitic agent, has been shown to be effective against SARS-CoV-2 in vitro.[700] It is unclear whether the doses necessary to achieve antiviral activity against SARS-CoV-2 are attainable in humans.[701] 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 randomized 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.[702] High-dose intravenous vitamin C is being trialed in some centers for the treatment of severe COVID-19.[703] 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.[704] A pilot randomized 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.[705] 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.[706][707][708] Vitamin D is being trialed in patients with COVID-19.[709][710] However, there is no evidence to recommend vitamin D for the prophylaxis or treatment of COVID-19 as yet.[711] A pilot randomized controlled trial found that high-dose calcifediol, a vitamin D3 analog, significantly reduced the need for intensive care unit treatment in hospitalized patients, and may improve clinical outcomes.[712] 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.[713] 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.[304][305][306] 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.[714]

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.[715] A meta-analysis found that Chinese medicine combined with conventional treatment significantly improved clinical efficacy compared with conventional treatment alone; however, high-quality, multiple-center, large-sample randomized controlled trials are needed.[716]

Hyperbaric oxygen

Preliminary evidence suggests that hyperbaric oxygen treatment has been successfully used to treat deteriorating, severely hypoxemic patients with severe COVID-19.[717][718] Clinical trials are currently recruiting.[719][720]

Nitric oxide

Studies indicate that nitric oxide may help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication in epithelial cells.[721] 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.[722][723] The manufacturer has requested emergency-use authorization 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.[724]

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 randomized trials for patients with COVID-19.[725]

Tradipitant

A neurokinin 1 antagonist that is being trialed for the treatment of neurogenic inflammation of the lung secondary to SARS-CoV-2 infection. Interim analysis of the ODYSSEY study found that hospitalized patients improved sooner when treated with tradipitant compared with placebo. The trial is ongoing.[726][727]

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