Clinical Trials For COVID-19

Clinical Trials For COVID-19


The COVID-19 pandemic continues to spread globally despite lockdowns and restrictions. The lack of definitive treatment for the deadly virus has propelled research towards a multipronged approach to mitigate transmission, morbidity, and mortality. In response to the global emergency, clinical trials assessing the efficacy and safety of interventions to manage the deadly disease are emerging at an unprecedented rate. Vaccines are viewed as the best strategy to handle the pandemic, but the need of the hour is finding therapies to treat those already infected. Two main approaches being utilized in this direction are:

  • Repurposing already existing therapeutic medicines.

  • Fast-tracking new drug development against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the virus that causes COVID-19

Repurposing Medicines

In drug repurposing, the focus is on medicines that have already been approved for another disease or are in a particular stage of clinical development. Repurposing drugs is a viable option as they can be converted more quickly than a completely new development. Medicines currently being repurposed for their suitability against Covid-19 belong to one of the following three groups:

  • Antivirals

  • Immunosuppressants/Immunomodulators

  • Medicines for lung patients

Antiviral medicines

Antiviral agents are designed to block the reproduction of the viruses or prevent them from entering lung cells. Antivirals being repurposed include drugs that were originally developed for hepatitis C, influenza, Ebola, Severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome (MERS) and human immunodeficiency viruses (HIV). Major drugs in this category which are being tested are Remdesivir, Leronlimab, Lopinavir/Ritonavir, and Favipiravir. Trials are also testing hydroxychloroquine and chloroquine, a well-known anti-malaria medicine proposed to have antiviral and immunomodulatory properties.

Immunosuppressants/Immunomodulators

For the latter phase of recovery, hospitalized patients with COVID-19 can develop a syndrome of dysregulated and systemic immune overactivation that worsens acute respiratory distress syndrome and can lead to multisystem organ failure. Hence, several studies aim to curb excessive immune reactions in terminally ill patients. Trials are testing immunosuppressants such as

  • Tocilizumab (anti-IL-6 used in the treatment of rheumatoid arthritis)

  • Adalimumab (anti-TNF)

  • Eculizumab (anti-C5)

  • Sarilumab (anti-IL-6)

  • Ixekizumab (anti-17A)

  • Fingolimod (sphingosine-1-phosphate receptor modulator, used against multiple sclerosis)

Trials are also investigating immune stimulation properties of the following drugs:
  • Tocilizumab (anti-IL-6 used in the treatment of rheumatoid arthritis)

  • Anti-PD-1 antibody camrelizumab

  • Recombinant IL-2, CSA0001 (LL-37 antiviral peptide with immunomodulatory functions)

  • CD24FC [fusion protein that prevents Toll-like receptor (TLR) activation and activates immunosuppressive Siglec signaling]

  • Recombinant human granulocyte colony-stimulating factor (rhG-CSF)


Medicines for lung manifestations

Medicines are also being explored to tackle lung manifestations of COVID-19, such as idiopathic pulmonary fibrosis. One such example is pirfenidone from Roche. Pirfenidone is an anti-fibrotic, anti-inflammatory drug that counteracts the scarring of damaged lung tissue.

New Drug Development against SARS-Cov-2 Apart from repurposing drugs, several companies are testing new medicines against Covid-19. In this category, three main approaches are being harnessed:

  • Using existing early-stage projects for antiviral medicines

  • Convalescent plasma - Antibodies for passive immunization

  • New development of suitable active substances

    Clinical Trials Assessing the Efficacy and Safety of Clinical Candidate Interventions

    As of 23 May 2020, over 2845 clinical trials have been registered on WHO’s International Clinical Trials Registry Platform (ICTRP). Some of the major randomized clinical trials that have been published investigated the following interventions:

    • Lopinavir–ritonavir compared with standard of care

    • Hydroxychloroquine compared with best supportive care

    • Favipiravir compared with arbidol

    • Lopinavir–ritonavir compared with arbidol


    Apart from the above, many non-randomized trials have investigated hydroxychloroquine versus hydroxychloroquine combined with azithromycin.

    Computer models speculate that the new coronavirus would not bind to ACE2 as well as the SARS virus. However, the researchers found that the spike protein of the new coronavirus bound far better than computer predictions, likely because of natural selection on ACE2 that enabled the virus to take advantage of a previously unidentified alternate binding site. As per the researchers, this aspect provides strong evidence that that deadly virus was not human-made in a lab - any bioengineer trying to design a coronavirus that threatened human health probably would never have chosen this particular conformation for a spike protein.

    Remdesivir - Positive Early Results from Covid-19 Clinical Trials

    Remdesivir is one of the first drugs to demonstrate positive clinical trial data in COVID-19. Remdesivir is an antiviral agent originally developed for hepatitis C, however, the drug has undergone a lot of repurposing since its initial development. Remdesivir was studied as a treatment for the Ebola virus and now, its use is being explored in Covid-19.

    On 29 April 2020, Gilead Sciences announced topline results from the Phase 3 SIMPLE trial. The phase III trial demonstrated similar clinical improvement in patients receiving a 10-day treatment of Remdesivir to those receiving a five-day treatment. More than 50 % of the patients in both treatment groups were discharged from the hospital by Day 14. At Day 14, clinical recovery was achieved in 64.5% of the patients in the 5-day treatment group and 53.8% in the 10-day treatment group.

    Way Forward - The slow mutation rate of SARS-CoV-2 means that changes will emerge over the years

    Hydroxychloroquine in COVID–19 - Hype or hope?

    While several trials for COVID-19 offer hope, many have failed to demonstrate encouraging results. Hydroxychloroquine recently failed to meet endpoints and saw adverse events in a retrospective study. Patients treated with hydroxychloroquine also had a higher mortality rate in clinical trials in the US.

    As per a multinational registry analysis, published on 22 May 2020 in the Lancet, there is no evidence of the benefit of hydroxychloroquine or chloroquine when used either alone or with a macrolide. The study states that previous evidence supporting hydroxychloroquine or chloroquine was derived from either small anecdotal studies or inconclusive small randomized trials. The registry comprised data from 671 hospitals in six continents and included patients hospitalized between 20 December 2019, and 14 April 2020, with a positive laboratory finding for SARS-CoV-2. The authors concluded that their findings suggest not only an absence of therapeutic benefit but also potential harm with the use of hydroxychloroquine or chloroquine drug regimens in hospitalized patients with COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for the treatment of COVID-19.

    Although the development of vaccines against the new coronavirus is proceeding at an unprecedented pace, it is unlikely that they will be available for mass vaccination as early as 2020. Therefore, eyes are fixed on effective medicines which can be used to treat those already infected more quickly.




    References

    • WHO, International Clinical Trials Registry Platform (ICTRP). Available at: https://www.who.int/ictrp/en/ Accessed on: 23 May 2020.

    • Thorlund K, Dron L, Park J, et al. A real-time dashboard of clinical trials for COVID-19. Available at: https://www.thelancet.com/journals/landig/article/PIIS2589-7500(20)30086-8/fulltext#seccestitle10. Accessed on: 23 May 2020.

    • Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci). 2020;49(2):215‐219. https://www.thelancet.com/journals/landig/article/PIIS2589-7500(20)30086-8/fulltext#seccestitle10

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