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



Frequently Asked Questions

What is an “orphan drug” as per the New Drugs and Clinical Trial Rules, 2019?

“Orphan drug” means a drug intended to treat a condition which affects not more than five lakh persons in India.

The extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible if following conditions are met: Similarity with respect to quality has been proven to reference biologic Similarity with respect to preclinical assessment has been proven to reference biologic Clinical safety and efficacy is proven in one indication Mechanism of action is same for other clinical indications Involved receptor(s) are same for other clinical indications New indication not mentioned by innovator will be covered by a separate application.

The permission to initiate clinical trial granted in Form CT-06 or automatic approval in Form CT 4A shall remain valid for a period of 2 years from the date of its issue, unless extended by the CLA.

An audio-video recording of the informed consent process in case of vulnerable subjects in clinical trials of New Chemical Entity or New Molecular Entity including procedure of providing information to the subject and his understanding on such consent, shall be maintained by the investigator for record.

Yes. Before enrolment of first participant in any clinical trial, registration in CTRI is mandatory

The three tier mechanism comprises the following authorities: 1. Institutional Biosafety Committee (IBSC) at the Institute/ company – To ensure biosafety on-site 2. Review Committee on Genetic Manipulation (RCGM) in the Department of Biotechnology - Managed genetically engineered cell banks 3. Genetic Engineering Appraisal Committee (GEAC) in the Ministry of Environment & Forests (MoE&F)- for genetically modified organisms/ living modified organisms

Any person or institution or organisation having permanent establishment in India who intends to conduct clinical trial of a biological product can submit application for clinical trial.

After obtaining permission in CT-11 or CT-14 or CT-15 as the case may be, the person, who intends to manufacture the biological product for CT, shall make an application for grant of license to manufacture the biological product by the respective State Licensing Authority (SLA) in accordance with the provisions of the Act and the Drugs and Cosmetics Rules, 1945.

No. For biological product and substances discovered or developed in countries other than India, Phase I data should be submitted along with the application. After submission of Phase I data generated outside India to the Central Licensing Authority, permission may be granted to repeat Phase I trials or to conduct Phase II trials and subsequently Phase III trial concurrently with other global trials for that biological product.

“New drug” means, (i) a drug, including active pharmaceutical ingredient or phytopharmaceutical drug, which has not been used in the country to any significant extent, except in accordance with the provisions of the Act and the rules made thereunder, as per conditions specified in the labelling thereof and has not been approved as safe and efficacious by the Central Licencing Authority with respect to its claims; or (ii) a drug approved by the Central Licencing Authority for certain claims and proposed to be marketed with modified or new claims including indication, route of administration, dosage and dosage form; or (iii) a fixed dose combination of two or more drugs, approved separately for certain claims and proposed to be combined for the first time in a fixed ratio, or where the ratio of ingredients in an approved combination is proposed to be changed with certain claims including indication, route of administration, dosage and dosage form; or (iv) a modified or sustained release form of a drug or novel drug delivery system of any drug approved by the Central Licencing Authority; or (v) a vaccine, recombinant Deoxyribonucleic Acid (r-DNA) derived product, living modified organism, monoclonal anti-body, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug; Explanation: The drugs, other than drugs referred to in sub-clauses (iv) and (v), shall continue to be new drugs for a period of four years from the date of their permission granted by the Central Licencing Authority and the drugs referred to in sub-clauses (iv) and (v) shall always be deemed to be new drugs;

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