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Clinical research

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: 

  • 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) 
  • Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19 (Skipper et al. 16 July 2020)
  • New therapy added: Opaganib - selective sphingosine kinase-2 (SK2) inhibitor

Man on oxygen ss20

Source: Shutterstock.com

People hospitalised with COVID-19 often require oxygen therapy

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.

 

Antivirals

Remdesivir ss20

Source: Shutterstock.com

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

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;
  • Recommended for use in COVID-19 in several countries, including Italy, France;
  • 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;
  • Approved for the treatment of rheumatoid arthritis and lupus.

Evidence

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

  • 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).

Ongoing trials

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

Umifenovir

  • Antiviral treatment used for influenza infection in Russia and China;
  • Proposed as a standard care option for COVID-19 based on its mechanism of action and its effects in treating influenza-associated pneumonia;
  • In vitro inhibitory activity against SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS)

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

Immune modulators

Dexamethasone ss20

Source: Shutterstock.com

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

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

  • 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

  • RECOVERY;
  • REMAP-CAP.

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

  • No significant difference in time to clinical improvement within 28 days, mortality or time to hospital discharge in patients treated with convalescent plasma. Trial was terminated early and may have been underpowered to detect a clinically important difference (Li et al, 3 June 2020).

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 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.

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.

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;
  • There are no well-controlled published studies on the efficacy and safety of tocilizumab for the treatment of COVID-19; however, numerous clinical trials are planned or under way globally.

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

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.

Ongoing trials

Anakinra

Ongoing trials

  • REMAP-CAP.

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.

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.

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.

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

Gemtuzumab ozogamicin

  • Monoclonal antibody that binds to CD33-expressing tumour cells to induce cell cycle arrest and apoptotic cell death;
  • Indicated for CD33-positive acute myeloid leukaemia.

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 irritable bowel syndrome;
  • Currently being investigated to see if it can help manage inflammation associated with COVID-19.

Ongoing trials

  • CATALYST.

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).

Ongoing trials

Medi3506

  • Interleukin-33 monoclonal antibody developed for skin disorders.

Ongoing trials

  • ACCORD.

Antiviral antibody cocktail

  • Several companies are developing novel monoclonal antibodies to bind to and neutralise the SARS-CoV-2 virus;
  • This ‘antiviral antibody cocktail’ contains two antibodies and trials will investigate whether the therapy can improve the outcomes for COVID-19 patients;
  • It will also be tested as a preventive therapy in those who are healthy but at high risk of getting sick because they work in a healthcare setting or have been exposed to an infected person.

Ongoing trials

Other or multiple mechanisms

Colchicine 2 ss20

Source: Shutterstock.com

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

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

  • Participants who received colchicine had statistically significant improved time to clinical deterioration compared with a control group that did not receive colchicine. However, the authors said that the findings should be considered only hypothesis-generating, given the low enrolment and event rates (Deftereos et al, 24 June 2020).

Ongoing trials

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

  • Severity of COVID-19 is not associated with the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers.

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.

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.

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.

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.

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

Opaganib

  • Selectively inhibits sphingosine kinase-2 (SK2), a lipid-signalling molecule that promotes cancer growth
  • Currently under investigation for oncology, inflammatory and gastrointestinal indications
  • Pre-clinical studies have shown opaganib to have anti-inflammatory and anti-viral activity
  • In vivo studies have shown opaganib to decrease fatality rates from influenza

Ongoing trials:

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

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2020.20208126

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