Everything you need to know about the COVID-19 therapy trials

There are thousands of clinical trials investigating treatments and preventative measures for COVID-19.

Latest: 

Man on oxygen ss20
People hospitalised with COVID-19 often require oxygen therapy

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Researchers around the world are working at record speed to find the best ways to treat and prevent COVID-19, from investigating the possibility of repurposing existing drugs to searching for novel therapies against the virus.

Current approaches to COVID-19 therapies generally fall into two categories: antivirals — which prevent the virus from multiplying — and immune modulators — which help the immune system to fight the virus or stop it from overreacting dangerously. Some potential therapies act in a different way or via multiple mechanisms.

There are thousands of clinical trials of COVID-19 therapies taking place across the world. On 15 June 2020, the European Medicines Agency said it was in discussion with the developers of 132 potential COVID-19 treatments​[1]​.

This article collates the main treatments being studied, the evidence supporting their use and the trials they are being evaluated in. It will be updated on a regular basis.

Only evidence from randomised controlled trials comprising more than 100 participants is included, with the exception of select observational studies that have had a significant influence on ongoing research.

Contents

Antivirals:

Immune modulators:

Other or multiple mechanisms:

Antivirals

Image of "Remdesivir is a broad-spectrum antiviral which was originally developed to treat hepatitis C. It was the first COVID-19 treatment to be made available for use in the UK outside a clinical trial."
Remdesivir is a broad-spectrum antiviral which was originally developed to treat hepatitis C. It was the first COVID-19 treatment to be made available for use in the UK outside a clinical trial

Source: Shutterstock.com

Remdesivir

Evidence

Ongoing trials

Chloroquine/hydroxychloroquine

  • Antimalarials with in vitro activity against various viruses, including SAR-CoV-2 — the virus that causes COVID-19;
  • Anecdotal evidence in humans;
  • The US Food and Drug Administration has cautioned against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems;
  • In June 2020, all UK clinical trials using hydroxychloroquine to treat or prevent COVID-19 were instructed by the Medicines and Healthcare products Regulatory Agency (MHRA) to stop recruiting further participants;
  • Approved for the treatment of rheumatoid arthritis and lupus.

Evidence

  • Neither remdesivir nor hydroxychloroquine affected viral clearance in hospitalized patients with COVID-19 (Barratt-Due et al, 13 July 2021);
  • Neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19–associated hospitalisation or other secondary clinical outcomes, a randomised controlled trial has concluded (Reis et al, 22 April 2021);
  • WHO guideline development panel make a strong recommendation against the use of hydroxychloroquine for individuals who do not have COVID-19 (2 March 2021); 
  • Rigorous randomised controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection (Barnabas et al, 8 December 2020);
  • Interim results from the Solidarity trial suggest that remdesivir has little or no effect on mortality in patients who are hospitalised with COVID-19 (WHO Solidarity Trial Consortium, 2 December 2020); 
  • Post-exposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic COVID-19 in healthy persons exposed to a PCR-positive case patient (Mitjà et al. 24 November 2020); 
  • Among adults hospitalised with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14 (Self et al, 9 November 2020);
  • Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed COVID-19 or COVID-19-compatible illness among healthcare workers (Rajasingham et al, 17 October 2020);
  • Among patients hospitalised with COVID-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care (The RECOVERY collaborative group, 8 October 2020);
  • Among hospital-based health care workers, daily hydroxychloroquine did not prevent SARS-CoV-2 infection, although the trial was terminated early and may have been underpowered to detect a clinically important difference (Abella et al, 30 September 2020)  
  • Among patients hospitalised with mild-to-moderate COVID-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care (Cavalcanti et al, 23 July 2020) 
  • Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19 (Skipper et al, 16 July 2020)
  • UK Medicines and Healthcare products Regulatory Agency (MHRA) suspends recruitment to COVID-19 hydroxychloroquine trials (5 June 2020)
  • Preliminary results from ‘Randomised Evaluation of COVID-19 Therapy’ (RECOVERY) trial (5 June 2020): no significant difference in mortality rate at 28 days (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98–1.26]; P =0.10);
  • Hydroxychloroquine did not prevent illness compatible with COVID-19 or confirmed infection when used as postexposure prophylaxis within four days after exposure (Boulware et al, 3 June 2020);
  • No evidence of benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias (Mehra et al, 22 May 2020). Study retracted by The Lancet on 5 June 2020 following concerns about the data;
  • Not enough data available to support the routine use of hydroxychloroquine and chloroquine as therapies for COVID-19 (Chowdhury et al, 29 May 2020);
  • Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone (Tang et al, 14 May 2020).

Ongoing trials

Amodiaquine

  • An antimalarial similar in structure and activity to chloroquine; effective against some chloroquine-resistant strains;
  • Found to be highly effective at preventing viral entry; these results have been validated in cultured cells and in a small animal model of COVID-19 using infectious SARS-CoV-2 virus. 

Ongoing trials

Artesunate

  • A water soluble derivative of artemisinin used in the treatment of severe malaria;
  • Artemisinin-based combination therapies have demonstrated in vitro inhibition of SARS-CoV-2 as well as anti-inflammatory effects.

Ongoing trials

Lopinavir/ritonavir combination

  • HIV type 1 aspartate protease inhibitors, indicated for treatment of HIV infection in combination with other antiretroviral drugs;
  • Lopinavir has in vitro inhibitory activity against SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS);
  • Ritonavir is combined with lopinavir to increase its half-life;
  • Recommended for use in COVID-19 in several countries, including Italy and France.

Evidence

  • Neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19–associated hospitalisation or other secondary clinical outcomes, a randomised controlled trial has concluded (Reis et al, 22 April 2021);
  • Interim results from the Solidarity trial suggest that remdesivir has little or no effect on mortality in patients who are hospitalised with COVID-19 (WHO Solidarity Trial Consortium, 2 December 2020); 
  • In patients admitted to hospital with COVID-19, lopinavir–ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death (The RECOVERY collaborative group, 5 October 2020). 
  • Following a review of emerging data from the RECOVERY trial, researchers concluded that there was no beneficial effect of lopinavir/ritonavir on 28-day mortality in patients hospitalised with COVID-19 compared to usual care alone (Horby et al, 29 June 2020);
  • Evidence that early treatment with triple antiviral therapy of interferon (IFN) beta-1b, lopinavir/ritonavir, and ribavirin — alongside standard care — is safe and shortens duration of viral shedding compared with lopinavir-ritonavir alone (average 7 days vs. 12 days), in patients with mild-to-moderate COVID-19 (Hung et al, 8 May 2020);
  • Some evidence that lopinavir/ritonavir initiation within 12 days after symptom onset is associated with shorter time to clinical improvement. No significant differences in reduction of viral RNA load, duration of viral RNA detectability, duration of oxygen therapy, duration of hospitalisation, or time from randomization to death. Lopinavir/ritonavir stopped early in 13 patients because of adverse effects (Cao et al, 7 May 2020).

Favipiravir

  • Broad-spectrum antiviral with in vitro activity against various viruses, including coronaviruses;
  • Licensed in Japan and China for treatment of influenza;
  • Not currently included in any of the UK trials for COVID-19.

Ongoing trials

Ribavirin

  • Broad-spectrum antiviral used to treat hepatitis C, respiratory syncytial virus (RSV) and bronchiolitis;
  • In vitro activity against SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS);
  • Some evidence of efficacy as an adjunct therapy in SARS;
  • Evidence from mouse models in SARS-CoV suggested it could increase infectivity.

Evidence

  • Evidence that early treatment with triple antiviral therapy of IFN beta-1b, lopinavir-ritonavir, and ribavirin — alongside standard care — is safe and shortens duration of viral shedding compared with lopinavir-ritonavir alone (average 7 days vs. 12 days), in patients with mild to moderate COVID-19 (Hung et al, 8 May 2020).

EIDD-2801

  • Investigational oral nucleoside analogue with broad-spectrum antiviral activity against RNA viruses, including influenza and coronaviruses like SARS and Middle East respiratory syndrome (MERS).

Ongoing trials

Niclosamide

  • Anti-helminthic drug with potential antiviral activity against SARS-CoV-2;
  • Unlicensed in the UK.

Ongoing trials

Nitazoxanide

  • A broad-spectrum antiparasitic and antiviral medication used for the treatment of various helminthic, protozoal, and viral infections;
  • Has yielded successful results in vitro against previous coronaviruses.

Evidence

  • In patients with mild COVID-19, symptom resolution did not differ between nitazoxanide and placebo groups after 5 days of therapy. However, early nitazoxanide therapy was safe and reduced viral load significantly (Rocco et al, 24 Dec 2020).

Ongoing trials

  • ANTICOV.

Oseltamivir

  • A neuraminidase inhibitor approved for the treatment of influenza A and B;
  • Several clinical trials are evaluating the effectiveness of oseltamivir in treating SARS-CoV-2 both alone and in combination with other drugs.

Ongoing trials

Ivermectin

Evidence

  • A randomised, double-blind, placebo-controlled study found that ivermectin had no significant effect on preventing hospitalisation of patients with COVID-19. Patients who received ivermectin required invasive mechanical ventilatory support earlier in their treatment. No significant differences were observed in any of the other secondary outcomes (Vallejos et al, 2 July 2021);
  • Patients with mild-to-moderate COVID-19 infection treated with ivermectin plus doxycycline recovered earlier, were less likely to progress to more serious disease, and were more likely to be COVID-19 negative by RT-PCR on day 14 (Mahmud et al, 13 May 2021);
  • Findings from a randomised controlled trial of 476 patients do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand effects on other clinically relevant outcomes (López-Medina et al, 4 March 2021);
  • Ivermectin is suggested to be a promising, effective and safe chemoprophylactic drug in the management of COVID-19 (Shoumann et al, 1 Feb 2021).

Ongoing trials

AT-527 

  • An orally administered, direct-acting antiviral currently in development;
  • Targets SARS-CoV-2 ribonucleic acid (RNA) polymerase (nsp12), a highly conserved gene responsible for both viral RNA replication and transcription;
  • It is anticipated that ATR-527’s antiviral activity will be effective against the emerging strains of the virus.

Ongoing trials

Immune modulators

Dexamethasone tablets
Dexamethasone was the first drug to be shown to improve survival in patients hospitalised with COVID-19

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Dexamethasone

  • Steroid that reduces inflammation by mimicking anti-inflammatory hormones produced by the body;
  • Indicated for the suppression of inflammatory and allergic disorders;
  • Only suitable for people who are already in hospital and receiving oxygen or mechanical ventilation;
  • It is the first drug to be shown to improve survival in COVID-19;
  • Approved for NHS use by UK government.

Evidence

  • In patients hospitalised with COVID-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support (RECOVERY Collaborative Group, 25 February 2021).
  • Intravenous dexamethasone plus standard care, compared with standard of care alone, resulted in a statistically significant increase in the number of days alive and free of mechanical ventilation over 28 days. (Tomazini et al, 2 September 2020);
  • Preliminary results from the RECOVERY trial suggest that dexamethasone reduced deaths by 35% in ventilated patients and by 20% in other patients receiving oxygen only. There was no benefit among those patients who did not require respiratory support (Horby et al, 17 July 2020).

Ongoing trials

Hydrocortisone

  • Steroid that reduces inflammation by mimicking anti-inflammatory hormones produced by the body;
  • Used for a variety of conditions including adrenocortical insufficiency, rheumatoid arthritis, dermatitis, asthma and chronic obstructive pulmonary disorder;
  • Commonly used to manage septic shock in patients with COVID-19;
  • Evidence regarding corticosteroid use for severe COVID-19 is limited.

Evidence

  • Patients with severe COVID-19 who are treated intravenously with the steroid, hydrocorticosone, are up to 93% more likely to have a better outcome compared to patients who are not given the drug, principal findings from the REMAP-CAP trial suggest. However, the trial was stopped early and no treatment strategy met pre-specified criteria for statistical superiority (Angus et al, 2 September 2020); 
  • Low-dose hydrocortisone did not significantly reduce treatment failure in patients with COVID-19–related acute respiratory failure; however, the study was stopped early and was therefore likely underpowered (Dequin et al, 2 September 2020).

Ongoing trials

Budesonide (inhaled)

  • Inhaled budesonide is often used to treat asthma and chronic obstructive pulmonary disease, with no serious side-effects associated with short-term use;
  • In some patients with COVID-19, the body’s immune response to the virus can cause high levels of inflammation that can damage cells in the airways and lungs. Inhaling budesonide into the airways targets anti-inflammatory treatment where it is needed most, and can potentially minimise any lung damage that might otherwise be caused by the virus.

Evidence

Ongoing trials

Convalescent plasma

  • Antibody-rich plasma of someone who has recovered from COVID-19;
  • There is some evidence suggesting possible benefits of convalescent plasma in patients with COVID-19, but available data to date are largely from case reports or series; confirmation from additional randomised controlled studies is required (Malani et al, 12 June 2020);
  • Has been approved for use in critically ill patients in the United States and UK.

Evidence

Ongoing trials

AZD7442

  • AZD7442 is a combination of two long-acting antibodies (LAABs) derived from convalescent patients after SARS-CoV-2 infection;
  • LAABs mimic natural antibodies and have the potential to treat and prevent disease progression in patients already infected with the virus, as well as to be given as a preventative intervention prior to exposure to the virus;
  • In pre-clinical experiments the two LAABs have been shown to block the binding of the SARS-CoV-2 virus to host cells and protect against infection in cell and animal models of disease.

Evidence

  • Late-stage trial data from AstraZeneca, released on 20 August 2021, suggested that its antibody therapy reduced the risk of people developing any COVID-19 symptoms by 77%. The company said that it was targeting conditional approval in major markets well before the end of the year.

Ongoing trials

Azithromycin

  • Macrolide antibiotic;
  • Some in vitro activity against some viruses, such as influenza A and zika;
  • May reduce cytokine levels, which can promote inflammation.

Evidence

  • Among outpatients with SARS-CoV-2 infection, treatment with a single dose of oral azithromycin compared with placebo did not result in a greater likelihood of being free of symptoms at day 14 (Oldenburg et al, 16 July 2021);
  • In patients with mild-to-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death (Hinks et al, 9 July 2021);
  • Published findings from the PRINCIPLE trial do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community (PRINCIPLE Trial Collaborative Group, 4 March 2021);
  • Azithromycin should not be used in the management of confirmed or suspected COVID-19, the Department of Health and Social Care has advised (1 February 2021);
  • Preliminary analysis of data from the RECOVERY trial has revealed that there was no significant difference in the primary endpoint of 28-day mortality between azithromycin (19%) and usual care (19%). There was also no evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay (14 December 2020);
  • In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes (Furtado et al, 4 September 2020); 
  • Among patients hospitalized with mild-to-moderate COVID-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care (Cavalcanti et al, 23 July 2020). 

Ongoing trials

  • RECOVERY;
  • PRINCIPLE.

Doxycycline

  • A broad-spectrum tetracycline-class antibiotic used in the treatment of infections caused by bacteria and certain parasites;
  • Considered as a potential treatments for COVID-19 in the community due to its anti-inflammatory, antibacterial and possibly antiviral effects;
  • It has been reported that doxycycline lowers significantly proinflammatory cytokines, including interleukin-6. 

Evidence

  • In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19 (Butler et al, 27 July 2021);
  • Doxycycline should not be used in the management of confirmed or suspected COVID-19, the Department of Health and Social Care has advised (1 February 2021);
  • Interim analyses of data from the doxycycline arm of the PRINCIPLE trialconcluded that there was no beneficial effect in patients aged over 50 who are treated with doxycycline at home in the early stages of COVID-19. The researchers also found that the treatment did not reduce the time taken for people to first report that they feel recovered from COVID-19.

Ongoing trials

Interferons

  • Modulate immune response to some viral infections;
  • Only limited clinical trial data are currently available on the efficacy of IFNs for treatment of COVID-19;
  • Clinical trials are currently evaluating IFN beta-1a or IFN beta-1b, generally added to antivirals.

Evidence

  • Interim results from the Solidarity trial suggest that IFN beta-1a has little or no effect on mortality in patients who are hospitalised with COVID-19 (15 October 2020).
  • Results of a small randomised, double-blind, placebo-controlled, phase II pilot trial of inhaled nebulised interferon beta-1a (SNG001) in adults admitted to hospital with COVID-19 suggest a greater odds of improvement on the WHO Ordinal Scale for Clinical Improvement (OSCI) (odds ratio 2·32 [95% CI 1·07–5·04]) on day 15 or 16 versus placebo. and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (hazard ratio 2·19 [95% CI 1·03–4·69]). (Monk et al, 12 November 2020).

Ongoing trials

Tocilizumab

  • Monoclonal antibody that inhibits interleukin-6 (IL-6), which is vital in the immune response to SAR-CoV-2;
  • Indicated for treatment of rheumatoid arthritis;
  • May combat cytokine release syndrome in severely ill COVID-19 patients.

Evidence

Ongoing trials

Sarilumab

  • Monoclonal antibody that inhibits IL-6, which is vital in the immune response to SAR-CoV-2;
  • Indicated for treatment of rheumatoid arthritis;
  • May combat cytokine release syndrome and pulmonary symptoms in severely ill COVID-19 patients.

Evidence

Ongoing trials

  • REMAP-CAP.

Regdanvimab

  • A monoclonal antibody with activity against SARS-CoV-2;
  • Designed to attach to the spike protein of SARS-CoV-2 – when it attaches to the spike protein, the ability of the virus to enter the body’s cells is reduced;
  • This is expected to reduce the need for hospitalisation in patients with mild to moderate COVID-19.

Evidence

Canakinumab

  • Inhibits interleukin-1 (IL-1), which is vital in the immune response to SAR-CoV-2;
  • Indicated to treat certain periodic fever syndromes and gouty arthritis;
  • Potential to treat cytokine release syndrome in severely ill COVID-19 patients.

Evidence

  • Among patients hospitalised with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without invasive mechanical ventilation at day 29 (Caricchio et al, 20 July 2021);
  • An interim analysis of the CAN-COVID trial showed the drug did not meet the primary endpoint of clinical response, defined as survival without the need for mechanical ventilation up to day 29. The drug also failed on a key secondary endpoint, reduction in COVID-19-related death within four weeks after the treatment period.

Anakinra

Evidence

Ongoing trials

  • REMAP-CAP;
  • RECOVERY.

Baricitinib

  • Janus-associated tyrosine kinase (JAK) 1 and JAK 2 inhibitor;
  • Modulates the immune response by regulating overactive signalling through the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway;
  • Indicated for treatment of rheumatoid arthritis;
  • May potentially combat cytokine release syndrome (CRS) in severely ill patients;
  • Currently no known published controlled clinical trial evidence supporting efficacy or safety in patients with COVID-19.

Evidence

  • Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19 (Marconi et al, 1 September 2021);
  • Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with COVID-19, notably among those receiving high-flow oxygen or non-invasive ventilation. The combination was associated with fewer serious adverse events (Kalil et al, 11 December 2020).

Ongoing trials

Ruxolitinib

  • Selective inhibitor of JAK 1 and JAK 2;
  • Modulates the immune response by regulating overactive signalling through the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway;
  • Indicated for specialist treatments;
  • May combat CRS in severely ill patients;
  • Currently no known published clinical trial evidence supporting efficacy or safety in patients with COVID-19.

Evidence

Ongoing trials

Tofacitinib

  • An orally administered selective inhibitor of JAK 1 and JAK 3, with functional selectivity for JAK2;
  • Also modulates the action of interferons and interleukin-6, decreasing the release of cytokines by type 1 and type 17 helper T cells, which are implicated in the pathogenesis of the acute respiratory distress syndrome (ARDS);
  • Thought that the action of tofacitinib may ameliorate progressive, inflammation-driven lung injury in hospitalised patients with COVID-19.

Evidence

  • Among patients hospitalised with COVID-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo (Guimarães et al, 16 June 2021).

Ongoing trials

Acalabrutinib

  • Bruton’s tyrosine kinase inhibitor;
  • In clinical development for people with chronic lymphocytic leukaemia, approved for this use in the United States;
  • Early clinical data have shown it can lead to a decrease in inflammation and reduction in the severity of COVID-19-induced respiratory distress.

Evidence

Ongoing trials

Imatinib

  • A tyrosine kinase inhibitor used in the treatment of some types of leukaemia, blood disorders and gastrointestinal stromal tumours;
  • Data suggest that imatinib may have anti-SARS-CoV-2 activity, either on-target through inhibition of ABL1/2 or off-target through a previously unrecognised protease-inhibiting effect.

Ongoing trials

Brensocatib

  • Reversible inhibitor of the dipeptidyl peptidase-1 enzyme, which is known to be associated with pathogen destruction and inflammatory mediation;
  • Not licensed in the UK;
  • Could be beneficial for ARDS in severely ill COVID-19 patients.

Ongoing trials

Ravulizumab

  • Recombinant monoclonal antibody;
  • Used routinely in blood diseases where complement activation destroys red blood cells;
  • Potential to treat CRS in severely ill COVID-19 patients.

Ongoing trials

Namilumab

  • Human immunoglobulin G1 monoclonal antibody currently in late-stage trials for the treatment of rheumatoid arthritis and ankylosing spondylitis;
  • Currently being investigated to see if it can help manage inflammation associated with COVID-19.

Ongoing trials

  • CATALYST.

Infliximab

  • Chimeric monoclonal antibody indicated to treat inflammatory conditions, including rheumatoid arthritis and inflammatory bowel disease;
  • Currently being investigated to see if it can help manage inflammation associated with COVID-19.

Ongoing trials

Adalimumab

  • An anti-tumour necrosis factor (TNF) drug already used for a wide-range of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease;
  • Recent studies of patients with COVID-19 have shown that patients already taking anti-TNF drugs for other conditions were less likely to be admitted to hospital.

Ongoing trials

Otilimab

  • Monoclonal antibody already in trials for the treatment of arthritis;
  • May be able to help to block the effects of one of the types of cytokine (known as GM-CSF).

Evidence

  • GlaxoSmithKline announced results from the phase II proof of concept OSCAR study with otilimab which showed that in patients of all ages treatment difference was not statistically significant between the otilimab and standard of care groups, but in analysis by age, patients 70 years and older had an increased chance of being alive and free of respiratory failure 28 days after treatment with otilimab compared to the standard care group (65.1% vs 45.9%);

Ongoing trials

Medi3506

  • Interleukin-33 monoclonal antibody developed for skin disorders.

Ongoing trials

  • ACCORD.

Monoclonal antibody cocktails

REGEN-COV

Evidence

  • RECOVERY trial results suggest that REGEN-COV reduces the risk of death and the length of hospital stay for seronegative (patients who had not mounted their own immune response) hospitalised patients with severe COVID-19 (16 June 2021);
  • Results from a phase III trial of recently infected asymptomatic COVID-19 patients found that REGEN-COV (casirivimab with imdevimab) decreased the overall risk of patients progressing to symptomatic COVID-19 by 31%; the trial’s primary endpoint. It also decreased the overall risk of progression by 76% after the third day, decreased the duration of symptoms and significantly reduced viral levels (12 April 2021);
  • Topline results from a phase III outcomes trial suggest that investigational REGEN-COV (casirivimab with imdevimab) significantly reduced the risk of hospitalisation or death by 70% (1,200 mg intravenous [IV]) and 71% (2,400 mg IV) compared to placebo. It also met all secondary endpoints, including the ability to reduce symptom duration (23 March 2021);
  • The European Medicines Agency’s Committee for Medicinal Products for Human Use concludes that REGN-COV2 can be used for the treatment of confirmed COVID-19 in patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19;
  • In an interim analysis, the REGN-COV2 antibody cocktail was found to reduce viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group (Weinreich et al. 17 December 2020);
  • Regeneron Pharmaceuticals, Inc. announces positive, prospective results from an ongoing Phase 2/3 seamless trial in the COVID-19 outpatient setting showing its investigational antibody cocktail, REGN-COV2, met the primary and key secondary endpoints. REGN-COV2 significantly reduced viral load and patient medical visits (28 October 2020).

Ongoing trials

Bamlanivimab plus etesevimab

Evidence

  • Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of COVID-19–related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load (Dougan et al, 14 July 2021); 
  • Eli Lilly announce new data from the BLAZE-1 Phase III study, demonstrating that bamlanivimab (LY-CoV555) 700mg and etesevimab (LY-CoV016) 1400mg together significantly reduced COVID-19 related hospitalizations and deaths (“events”) in high-risk patients recently diagnosed with COVID-19 (10 March 2021);
  • Treatment with bamlanivimab and etesevimab combination therapy, but not bamlanivimab monotherapy, resulted in a reduction in SARS-CoV-2 log viral load at day 11 in patients with mild to moderate COVID-19 (Gottlieb et al, 21 January 2021).

Ongoing trials

  • OPTIMISE-C19;

Bamlanivimab (monotherapy)

  • Bamlanivimab (LY-CoV555) is a potent neutralising IgG1 monoclonal antibody directed against the spike protein on SARS-CoV-2;
  • Designed to block viral attachment and entry into human cells, thus neutralising the virus, potentially preventing and treating COVID-19.

Evidence

  • A randomised phase III clinical trial including 966 participants, concluded that bamlanivimab monotherapy compared with placebo reduced the risk of COVID-19 in residents and staff of skilled nursing and assisted living facilities (Cohen et al, 3 June 2021);
  • Initial results from the BLAZE-2 trial suggest that nursing home residents randomised to bamlanivimab have up to an 80% lower risk of contracting COVID-19 versus residents in the same facility randomised to placebo (21 January 2021);
  • Treatment with bamlanivimab and etesevimab combination therapy, but not bamlanivimab monotherapy, resulted in a reduction in SARS-CoV-2 log viral load at day 11 in patients with mild to moderate COVID-19 (Gottlieb et al, 21 January 2021);
  • Interim analysis of the BLAZE-1 trial found that one of three doses (2800mg) of the neutralizing antibody, bamlanivimab, appeared to accelerate the natural decline in viral load over time in patients with mild or moderate COVID-19, whereas the other doses (700mg and 7000mg) administered had not by day 11 (Chen et al, 28 October 2020); 
  • The ACTIV-3 trial, which is evaluating multiple investigational agents in hospitalised patients with COVID-19, stopped randomising patients to treatment with LY-CoV555 based on an analysis suggesting that the antibody was not beneficial in this population (26 October 2020).

Ongoing trials

Etesevimab (monotherapy)

  • Etesevimab (LY-CoV016) is a recombinant human monoclonal neutralising antibody;
  • Targets the SARS-CoV-2 spike protein and blocks binding of the virus to the ACE2 host cell surface receptor;
  • Effective for both prophylactic and therapeutic venues against SARS-CoV-2 infection in rhesus macaques.

Ongoing trials

  • BLAZE-4;
  • BLAZE-1;
  • OPTIMISE-C19.

Sotrovimab

  • Sotrovimab (VIR-7831) is an investigational dual-action SARS-CoV-2 monoclonal antibody;
  • Preclinical data suggest it has the potential to both block viral entry into healthy cells and clear infected cells;
  • The antibody binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (the virus that causes SARS), indicating that the epitope is highly conserved, which may make it more difficult for resistance to develop.

Evidence

  • The European Medicines Agency starts a rolling review into VIR-7831 based on preliminary results from an ongoing study looking at the ability of the medicine to prevent hospitalisation or death in non-hospitalised patients with COVID-19 (7 May 2021);
  • An interim analysis of data from 583 patients enrolled in the COMET-ICE trial, demonstrated an 85% (p=0.002) reduction in hospitalisation or death in patients receiving VIR-7831 as monotherapy compared to placebo (10 March 2021).

Ongoing trials

Leronlimab

  • An investigational humanised monoclonal antibody targeted against the CCR5 receptor, which appears to play a central role in modulating immune cell trafficking to sites of inflammation;
  • Being looked at as a potential therapy in the treatment of triple negative breast cancer and HIV infection as well as COVID-19.

Ongoing trials

Risankizumab

  • Risankizumab is an anti-IL-23 monoclonal antibody developed by Boehringer Ingelheim and AbbVie;
  • Being investigated for the treatment of multiple inflammatory diseases, including psoriasis, Crohn’s disease, ulcerative colitis, atopic dermatitis and psoriatic arthritis;
  • Approved in the US in 2019 for the treatment of severe plaque psoriasis;
  • Will be tested in conjunction with the antiviral drug remdesivir, compared to a placebo plus remdesivir.

Ongoing trials

Lenzilumab

Ongoing trials

IMU-838

  • IMU-838 is a next-generation selective immune modulator that inhibits the intracellular metabolism of activated immune cells by blocking the enzyme, dihydroorotate dehydrogenase;
  • Investigational drug under development as an oral tablet formulation for the treatment of relapsing-remitting multiple sclerosis, inflammatory bowel disease and other chronic inflammatory and autoimmune diseases;
  • Also being investigated as a potential treatment option for COVID-19.

Ongoing trials

Other or multiple mechanisms

Image of "Colchicine is used for treating inflammation and pain in conditions such as gout and could help ameliorate COVID-19 complications"
Colchicine is used for treating inflammation and pain in conditions such as gout and could help ameliorate COVID-19 complications

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Colchicine

  • Medicine for treating inflammation and pain in conditions such as gout;
  • Could help ameliorate COVID-19 complications, but there is minimal anecdotal experience and clinical trial data reported to date in COVID-19.

Evidence

Ongoing trials

Dimethyl fumarate

  • An immunomodulatory drug thought to prevent NLRP3 inflammasome activation and the process of inflammatory cell death through its action on the protein, gasdermin D;
  • Licensed to treat relapsing remitting multiple sclerosis and plaque psoriasis as a long-term immunomodulatory agent and is generally well-tolerated with no major safety concerns;
  • Has demonstrated anti-viral and anti-inflammatory effects against SARS-CoV-2 in vitro.

Ongoing trials

  • RECOVERY

Angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers

  • Indicated for the treatment of hypertension and heart failure;
  • There have been suggestions that the drugs can increase both the risk of infection and the severity of SARS-CoV2, but data are lacking;
  • May also have a protective effect against lung damage.

Evidence

  • Results from a multicentre blinded randomised controlled trial for outpatients with mild symptomatic COVID-19 disease, losartan did not reduce hospitalisations, although assessment was limited by low event rate. Viral load was not statistically affected by treatment (Puskarich et al, 17 June 2021);
  • Severity of COVID-19 is not associated with the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers;
  • The BRACE CORONA trial, which tested temporarily stopping an ACE inhibitor/ARB for 30 days versus continuing ACE inhibitors/ARBs in patients who were taking these medications chronically and were hospitalised with a confirmed diagnosis of COVID-19, found no clinical difference, suggesting the medication should generally be continued for those with an indication (Lopes et al, presented at the European Society of Cardiology Congress 2020 on 1 September 2020).

Ongoing trials

Statins

  • Indicated for the treatment of cardiovascular disease;
  • Decrease inflammation, reduce blood clots, and prevent damage to endothelial tissue;
  • Some evidence they can act as antivirals;
  • Could potentially combat CRS in severely ill patients, but concrete data are lacking.

Ongoing trials

Aspirin

  • Triple effect of inhibiting virus replication, anticoagulation and anti-inflammatory.

Evidence

Ongoing trials

Clopidogrel

  • Anti-platelet drug that could help prevent blood-clots associated with COVID-19.

Ongoing trials

  • C-19-ACS.

Anticoagulants

  • Potential role of anticoagulation in specific COVID-19 patients for improved mortality.

Evidence

  • Anticoagulation with heparin could increase survival and reduce the need for organ support in patients hospitalised with moderate COVID-19, compared to usual care, results from three integrated platform trials – REMAP-CAP, ACTIV-4 and ATTACC – have suggested. In contrast, anticoagulation therapy did not improve outcomes if started when patients were already critically ill with COVID-19 (The ATTACC, ACTIV-4a, and REMAP-CAP Investigators, 4 August 2021);
  • Results of the INSPIRATION randomised clinical trial including 562 patients do not support routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients with COVID-19 admitted to the ICU (INSPIRATION investigators, 18 March 2021);
  • Early initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with COVID-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events (Rentsch et al. 11 February 2021). 

Ongoing trials

Bemcentinib

  • Selectively inhibits AXL kinase, which blocks viral entry and enhances the antiviral type I IFN response;
  • Investigational treatment for COVID-19;
  • Reported to exhibit potent anti-viral activity in pre-clinical models against several enveloped viruses, including Ebola and Zika virus.

Evidence

Ongoing trials

Omeprazole

  • Proton-pump inhibitor indicated for the treatment of gastroesophageal reflux disease (GORD);
  • Being investigated as an additive treatment for COVID-19.

Ongoing trials

  • C-19-ACS.

Famotidine

  • Histamine-2 receptor antagonist used in the treatment of GORD;
  • Some evidence to suggest it is associated with improved patient-reported outcomes in non-hospitalised patients with COVID-19.

Ongoing trials

Zilucoplan

  • Synthetic macrocyclic peptide inhibitor already in trial for potential treatment of the skeletomuscular disorder myasthenia gravis;
  • Could reduce damage to lung tissue caused by the virus.

Ongoing trials

  • ACCORD.

Ascorbic acid/vitamin C

  • Use of vitamin C could be effective in terms of mortality and secondary outcomes in patients with COVID-19 pneumonia due to its anti-inflammatory and antioxidant properties.

Evidence

  • Evidence from a randomised clinical trial of 214 patients suggests that treatment with zinc, ascorbic acid, or both does not affect SARS-CoV-2 symptoms (Thomas et al. 12 February 2021).

Ongoing trials

Vitamin D3

  • Vitamin D insufficiency is a potential risk factor for non-communicable and acute respiratory tract diseases, including viral infections;
  • It has been speculated that optimal serum levels of vitamin D may have immunomodulatory and anti-inflammatory properties, and could possibly benefit patients with COVID-19.

Evidence

  • Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19 (Murai et al, 17 February 2021).

Ongoing trials

Aviptadil

  • Synthetic form of human vasoactive intestinal peptide;
  • Indicated for treatment of erectile dysfunction;
  • Reduces inflammation in the lungs and protects the alveolar type II cells that are believed to be an entry route for the SARS-CoV-2 to invade the lungs.

Ongoing trials

Tradipitant

  • A neurokinin-1 receptor antagonist that works by blocking substance P, a neuropeptide secreted by neuronal cells and inflammatory cells that has multiple effects in different tissues;
  • Currently in clinical development for gastroparesis, motion sickness and atopic dermatitis.

Evidence

Ongoing trials

Nitric oxide

  • Nitric oxide (NO) inhalation has been used as a pulmonary vasodilator and has been found to have antiviral activity against other coronavirus strains;
  • Preliminary data support a microbicidal effect of high concentration inhaled NO;
  • NO is being investigated to see if it can prevent the deterioration to a severe form of COVID-19 when administered at an early stage of the disease.

Ongoing trials

Fluvoxamine

  • Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) used primarily for the treatment of obsessive–compulsive disorder;
  • It is thought that fluvoxamine may prevent clinical deterioration in patients with COVID-19 by stimulating the σ-1 receptor, which regulates cytokine production.

Evidence

  • Results from the TOGETHER trial, published as a pre-print on 26 August 2021, suggest that treatment with fluvoxamine (100mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19, reduced the need for extended emergency room observation or hospitalisation;
  • In a small preliminary study, adult outpatients with symptomatic COVID-19 treated with fluvoxamine, compared with placebo, had a lower likelihood of clinical deterioration over 15 days; however, determination of clinical efficacy would require larger randomized trials with more definitive outcome measures (Lenze et al. 12 November 2020). 

Ongoing trials

Proxalutamide

  • A non-steroidal anti-androgen developed for the treatment of prostate and breast cancer.

Evidence

Ongoing trials

Ruconest

  • A powder that is made up into a solution for injection; contains the active substance conestat alfa, a copy of the C1 esterase inhibitor protein that occurs naturally in the body;
  • Used in patients with hereditary angioedema that is linked to naturally low levels of a protein called C1 esterase inhibitor;
  • Studies are seeking to identify if the administration of ruconest can control or stop the systemic hyperinflammation syndrome or cytokine storm in COVID-19.

Ongoing trials

TRV027

  • An angiotensin II receptor type 1 (AT1 receptor) selective agonist;
  • Fights disruption within the renin-angiotensin system (RAS) by attaching to and rebalancing AT1 receptor activation;
  • Currently being investigated by multiple institutions as a potential treatment for acute lung injury contributing to ARDS and abnormal blood clotting in COVID-19 patients.

Ongoing trials

  • REMAP-CAP COVID-19 ACE2 RAS Modulation Domain trial (launched on 16 March 2021);
  • ACTIV-4d RAAS.

This article will be updated regularly as more information emerges. If there are any trials or treatments we have missed, let us know.

Other sources of information:

  1. 1
    Treatments and vaccines for COVID-19 . European Medicines Agency. 2020.https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines-covid-19 (accessed 2021).

Last updated
Citation
The Pharmaceutical Journal, September 2021;Online:DOI:10.1211/PJ.2021.20208126