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

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 randomized 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.

Remdesivir

Broad-spectrum antiviral originally developed to treat hepatitis C and was then tested against Ebola;
In vitro activity against SAR-CoV-2;
Some evidence of efficacy against COVID-19 in humans;
Available on a ‘compassionate use’ basis in many countries;
First COVID-19 treatment to be made available for use in the UK outside a clinical trial;
In the EU, remdesivir is now licensed for the treatment of COVID-19 in adults and adolescents with pneumonia requiring supplemental oxygen.

Evidence

Interim results from the Solidarity trial suggest that remdesivir has little or no effect on mortality in patients who are hospitalised with COVID-19 (15 October 2020);
Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and had evidence of lower respiratory tract infection (Beigel et al, 8 October 2020)
In moderate COVID-19, a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance (Spinner et al, 21 August 2020)
No significant efficacy difference between five and ten day courses of remdesivir in patients with severe COVID-19 (Goldman et al, 27 May 2020);
“No statistically significant differences” for mortality and serious adverse events in COVID-19 patients treated with remdesivir (National Institute for health and Care Excellence [NICE]);
First randomised trial of remdesivir suggests antiviral drug is not associated with significant clinical benefits, but numerical reduction in time to clinical improvement suggests more research needed (Wang et al, 29 April 2020).

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

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);
Interim results from the Solidarity trial suggest that hydroxychloroquine has little or no effect on mortality in patients who are hospitalised with COVID-19 (15 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 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

RECOVERY trial (recruitment to hydroxychloroquine arm closed as of 5 June 2020);
Chemoprophylaxis for COVID-19 infectious disease (the PROLIFIC trial);
An adaptive phase 2/3, randomised, open-label study assessing efficacy and safety of hydroxychloroquine for hospitalised patients with moderate to severe COVID-19;
‘Randomised, Embedded, Multifactorial, Adaptive Platform trial for Community-Acquired Pneumonia’ [REMAP-CAP] (paused by MHRA as of June 2020);
‘Platform Randomised trial of Interventions against COVID-19 In Older People’ [PRINCIPLE] (paused by MHRA as of June 2020);
‘Chloroquine Prevention of Coronavirus Disease (COVID-19) in the Healthcare Setting’; a randomised, placebo-controlled prophylaxis study (COPCOV) (given green light by MHRA to continue recruiting patients on 26 June 2020);
‘(Hydroxy)chloroquine Repurposing to Healthworkers for Novel Coronavirus Mitigation: An international, multi-site, Bayesian platform adaptive, randomised, double-blind, placebo-controlled trial assessing the effectiveness of varied doses of oral chloroquine’ (CROWN CORONATION);
Prophylaxis for patients at risk of COVID-19 infection (PROTECT);
SOLIDARITY (recruitment to hydroxychloroquine arm closed as of 17 June 2020);
DISCOVERY;
Hydroxychloroquine or Diltiazem-Niclosamide for the Treatment of COVID-19 (HYDILIC);
Health Care Worker Prophylaxis Against COVID-19 (HERO).

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

Interim results from the Solidarity trial suggest that lopinavir–ritonavir has little or no effect on mortality in patients who are hospitalised with COVID-19 (15 October 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).

Ongoing trials

REMAP-CAP;
RECOVERY (recruitment to lopinavir/ritonavir arm closed as of 29 June 2020);
SOLIDARITY (recruitment to lopinavir/ritonavir arm closed as of 4 July 2020);
DISCOVERY;
Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment.

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:

Clinical Study of Arbidol Hydrochloride Tablets in the Treatment of Pneumonia Caused by Novel Coronavirus

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

‘COVID-19 First in Human Study to Evaluate Safety, Tolerability and Pharmacokinetics of EIDD-2801 in Healthy Volunteers’

Niclosamide

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

Ongoing trials

HYDILIC;
Niclosamide for mild-to-moderate COVID-19 (Not yet recruiting).

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

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

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

RECOVERY;
REMAP-CAP.

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

Hydrocortisone for COVID-19 and Severe Hypoxia (COVID STEROID).

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 difference in 28 day mortality or progression to severe disease among patients with moderate COVID-19 treated with convalescent plasma along with best standard of care compared with best standard of care alone (Agarwal et al, 22 October 2020);
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

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.

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).

Ongoing trials

REMAP-CAP;
Comparing efficacy and safety of inhaled SNG001 to placebo;
SOLIDARITY;
DISCOVERY;
RECOVERY.

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.

Evidence

Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalised patients with COVID-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide (Stone et al, 21 October 2020);
Tocilizumab may reduce the need for mechanical and noninvasive ventilation or death by day 14 but not mortality by day 28 (Hermine et al, 20 October 2020);
For hospitalised adult patients with COVID-19 pneumonia and partial pressure of arterial oxygen to fraction of inspired oxygen (Pao₂/Fio₂) ratio of between 200-300mmHg, tocilizumab had no benefit on disease progression compared with standard care (Salvarani et al, 20 October 2020);
Patients who received tocilizumab were 44% less likely to progress to mechanical ventilation or death compared to patients who received placebo plus standard of care according to late-stage clinical data (18 September 2020).

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

Study of Efficacy and Safety of Canakinumab Treatment for CRS in Participants With COVID-19-induced Pneumonia (CAN-COVID)

Anakinra

Inhibits IL-1, which is vital in the immune response to SAR-CoV-2;
Indicated for treatment of rheumatoid arthritis, Still’s disease and cryopyrin-associated periodic syndromes;
Might help to neutralise the cause of acute respiratory distress syndrome (ARDS) among patients with COVID-19;
Anakinra has been used (off label) for cytokine storm syndromes triggered by other viruses and is reported to be relatively well tolerated, with a favourable safety profile.

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

‘Superiority Trial of Protease Inhibition in COVID-19’ (STOP-COVID19).

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

TACTIC-R;
‘Efficacy and Safety Study of IV Ravulizumab in Patients With COVID-19 Severe Pneumonia’.

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

‘A Randomised Phase II Proof of Principle Multi-Arm Multi-Stage Trial Designed to Guide the Selection of Interventions for Phase III trials in Hospitalised Patients with COVID-19 Infection’ (CATALYST).

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.

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

Adalimumab for Coronavirus in Community Care (AVID-CC).

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

‘A Randomised, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Otilimab IV in Patients with Severe Pulmonary COVID-19-Related Disease’ (OSCAR).

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;
REGN-COV2 comprises two monoclonal antibodies, REGN10933 and REGN10987, and was designed specifically by Regeneron scientists to block infectivity of SARS-CoV-2.

Ongoing trials

RECOVERY (REGN-COV2);
‘Safety, Tolerability and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for Hospitalised Adult Patients with COVID-19’;
Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-CoV-2 Monoclonal Antibodies for the Treatment of Ambulatory Adult Patients With COVID-19;
Phase III trial will evaluate the use of the antibody cocktail, REGN-COV2, to prevent infection among uninfected people who have had close exposure to a COVID-19 patient;
REGN-COV2 has also moved into the Phase 2/3 portion of two adaptive Phase 1/2/3 trials testing the cocktail’s ability to treat hospitalised and non-hospitalised (or “ambulatory”) patients with COVID-19.

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

Study to Evaluate the Efficacy and Safety of Leronlimab for Patients With Severe or Critical Coronavirus Disease 2019 (COVID-19).

LY-CoV555/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.

Ongoing trials

LY-CoV016/etesevimab

Also known as JS016, 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

A Study of LY3819253 (LY-CoV555) and LY3832479 (LY-CoV016) in Participants With Mild to Moderate COVID-19 Illness (BLAZE-1).

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

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;
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

‘Preventing Cardiac Complication of COVID-19 Disease With Early Acute Coronary Syndrome Therapy: A Randomised Controlled Trial’ (C-19-ACS).

Aspirin

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

Ongoing trials

C-19-ACS;
‘Protective Effect of Aspirin on COVID-19 Patients’ (PEAC).

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

A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID 19 in Hospitalised Patients (ACCORD-2-001).

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

‘Multi-Site Adaptive Trials for COVID-19’.

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:

Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia

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

Interim analysis of the ODYSSEY study demonstrated that hospitalised patients with COVID-19 pneumonia improved sooner when treated with tradipitant as compared to placebo (18 August 2020).

Ongoing trials

ODYSSEY: A Study to Investigate the Efficacy of Tradipitant in Treating Severe or Critical COVID-19 Infection

AZD1656

A glucokinase activator that has been shown to reduce blood glucose for up to four months in humans;
Has also been shown to activate the migration of T regulatory cells to sites of inflammation in preclinical experiments;
May prevent the development of cardiorespiratory complications observed in hospitalised patients with COVID-19;
AZD1656 has already undergone phase ll trials for use in type 2 diabetes and is currently under clinical investigation for renal transplant rejection.

Ongoing trials

AZD1656 in Diabetic Patients Hospitalised With Suspected or Confirmed COVID-19 (ARCADIA)

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

Razuprotafib

Investigational drug that activates Tie2 receptor proteins on the surface of endothelial cells to bind to angiopoietins; a key pathway in the formation, repair and stabilisation of blood vessels;
May prevent and treat respiratory distress in COVID-19 patients;
Pre-clinical studies and clinical data suggest promise for the drug in aiding COVID-19 patients.

Ongoing trials:

A Study to Evaluate the Safety and Efficacy of Razuprotafib, a Novel Tie 2 Activator, in Hospitalized Subjects With Moderate to Severe Coronavirus Disease 2019 (COVID-19) (RESCUE)

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

PJ Pod · Post-pandemic pharmacy: a brave new world?

References:

^[1] European Medicines Agency. 2020. Available at: https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines-covid-19 (accessed June 2020)

Other sources of information:

American Society of Health-System Pharmacists: https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-Evidence-Table.ashx?la=en&hash=B414CC64FD64E1AE8CA47AD753BA744EDF4FFB8C
National Institute of Health Research: https://www.nihr.ac.uk
ClinicalTrials.gov: https://clinicaltrials.gov
EU Clinical Trials Register: https://www.clinicaltrialsregister.eu

Citation: The Pharmaceutical Journal, PJ June 2020 online, online | DOI: 10.1211/PJ.2020.20208126

c/o: https://www.pharmaceutical-journal.com/news-and-analysis/features/everything-you-need-to-know-about-the-covid-19-therapy-trials/20208126.article

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Lopinavir/ritonavir combination

Evidence

Ongoing trials

Favipiravir

Ongoing trials

Umifenovir

Ongoing trials:

Ribavirin

Evidence

EIDD-2801

Ongoing trials

Niclosamide

Ongoing trials

Oseltamivir

Ongoing trials

Immune modulators

Dexamethasone

Evidence

Ongoing trials

Hydrocortisone

Evidence

Ongoing trials

Convalescent plasma

Evidence

Ongoing trials

Azithromycin

Evidence

Ongoing trials

Interferons

Evidence

Ongoing trials

Tocilizumab

Evidence

Ongoing trials

Sarilumab

Evidence

Ongoing trials

Canakinumab

Ongoing trials

Anakinra

Ongoing trials

Baricitinib

Ongoing trials

Ruxolitinib

Ongoing trials

Acalabrutinib

Ongoing trials

Brensocatib

Ongoing trials

Ravulizumab

Ongoing trials

Gemtuzumab ozogamicin

Ongoing trials

Namilumab

Ongoing trials

Infliximab

Ongoing trials

Adalimumab

Ongoing trials

Otilimab

Ongoing trials

Medi3506

Ongoing trials

Antiviral antibody cocktail

Ongoing trials

Leronlimab

Ongoing trials