key: cord-0961899-bgj618la authors: Akinbolade, Sola; Coughlan, Diarmuid; Fairbairn, Ross; McConkey, Glenn; Powell, Helen; Ogunbayo, Dapo; Craig, Dawn title: Combination therapies for COVID‐19: An overview of the clinical trials landscape date: 2021-10-17 journal: Br J Clin Pharmacol DOI: 10.1111/bcp.15089 sha: 4caa8a5d6d3fe4003570c11c6cecd61c585588c1 doc_id: 961899 cord_uid: bgj618la The COVID‐19 pandemic has driven an unprecedented level of global activity in drug discovery and clinical development for effective therapeutics targeting the coronavirus disease. There are currently 744 therapeutics being tested in 2879 clinical trials globally. Almost 90% of these clinical trials are focused on monotherapies. Combination therapies are the mainstay of antiviral therapeutics to increase the potency of the individual compounds and to combat the rapid evolution of resistance, although combination therapies have inherently complex clinical and regulatory development challenges. Increased understanding of the SARS‐CoV‐2 lifecycle and COVID‐19 pathology provides a scientific rationale for evaluating the effectiveness of different combinations. In this paper, we provide an overview of the current clinical trial landscape for combination therapeutics targeting COVID‐19 through weekly scanning of national and international clinical trial registries. Our analysis delves specifically into dual combination therapies in what can be defined as “pivotal clinical trials” (active, randomised, controlled and at least phase II), with a focus on new and repurposed therapeutic candidates that have shown positive signals and/or been granted authorisation for emergency use based on positive efficacy and safety data. Combination therapies have been invaluable for cancer chemotherapy, and chronic viral infections such as HIV using HAART (highly active antiretroviral therapy) to reduce the potential for resistance and also restrict levels of infection due to the weak efficacy of antivirals to clear the virus. 4, 5 Combination therapies have also been investigated in the treatment of acute viral infections such as influenza with the prediction to greatly reduce the development of rapid drug resistance, supress viral replication and achieve better efficacy and reduction in mortality than monotherapy. 4, 6, 7 Synergistic combinations, in which the efficacy is greater than that of the individual therapies, increases the chances for better treatment outcomes. These types of combinations frequently target a common or related pathway of the disease. Interventions may also be combined to treat two different pathologies of the disease, which may be particularly important for COVID-19. Unfortunately, the effectiveness of combining interventions to increase antiviral efficacy is not predictive and requires testing. The aim of this paper is to provide some insight from the current data on combination therapies in this rapidly changing field and their applications in clinical practice and future trials. (active); trial design (randomised); trial phase (phase II and above); estimated enrolment (trials with 100 or more participants); and trial location (UK, EU, USA, Australia or Canada). patients. 26 It was reported that participants in the trial were at the late stage of the disease, hence the probable ineffectiveness of the therapy. 27, 28 Remdesivir treatment was tested (as a standard of care) in dual combination with hyperimmune immunoglobulin (hIG), with both treatments targeting the virus: remdesivir inhibiting viral replication and the hIG neutralising SARS-CoV-2 (NCT04546581). This study, however, did not meet its endpoints as there was no reduction in the risk of disease progression in adults hospitalised with COVID-19. 29 Remdesivir and interferon beta-1a combination therapy is undergoing evaluation where the antiviral activity of remdesivir is combined with the dual antiviral and anti-inflammatory properties of interferon beta-1a (ACTT-3; NCT04492475). The efficacy of the combination is compared to treatment with remdesivir alone in hospitalised patients. 30 The result of this trial and other pivotal trials testing remdesivir in dual combination are yet to be published. With similar mechanism of action to remdesivir and shortened viral clearance time when compared with lopinavir/ritonavir, favipiravir may be another antiviral candidate for dual combination therapy trials. 31, 32 The timing of treatment may prove to be the key element in antiviral therapies, since antivirals are mostly effective at the early stage of the infection (incubation and early symptomatic phase) (Figure 1) . Neutralising monoclonal antibodies are under evaluation in clinical trials for treatment of COVID-19. 33 These antibodies bind and inactivate the spike glycoprotein (S protein) of SARS-CoV-2, hereby preventing entry of the virus particle into the host cell. 34 The efficacy of monoclonal antibodies has been tested as monotherapy and in combination, with encouraging results. Early results from trials exploring antibodies have shown significant benefit on survival and reduction in mortality for COVID-19 patients. 33, 35 Although the FDA revoked the EUA of bamlanivimab monotherapy due to a sustained increase in resistant variants of SARS-CoV-2, bamlanivimab is still undergoing evaluation in combination therapy trials. 36 In the BLAZE-1 study Other combination therapy trials testing neutralising antibodies are still ongoing. Elevations in IL-6 levels have been reported in many COVID-19 patients, and IL-6 inhibitors, such as tocilizumab, have been trialled to target the excessive inflammatory response (cytokine storm) of the immune system. 39, 40 Tocilizumab as a monotherapy has been reported to improve patient symptoms, shorten hospital stay, and reduce overall mortality from severe COVID-19. [40] [41] [42] Administration of tocilizumab at the beginning of inflammation has also been suggested to improve its efficacy. 43 However, the inclusion of tocilizumab in more combination therapy pivotal trials would be required to further investigate its effectiveness. Other anti-inflammatory interventions being tested in ongoing dual combination pivotal trials include baricitinib and colchicine. Baricitinib has previously been described to improve the clinical efficacy of remdesivir in combination when compared with remdesivir-only therapy. 23 It has also shown significant improvement in respiratory function in patients with COVID-19 pneumonia when combined with corticosteroids. 44 Colchicine has been reported to decrease cytokine production and improve patient survival when administered early in the disease process. 45 Colchicine may be considered as supportive treatment for hospitalised COVID-19 patients. The treatment pattern for COVID-19 is rapidly evolving and with focus on the clinical benefits of combination therapies, better treatment options will hopefully become available. Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20. 57 WHO declares COVID-19 a pandemic Challenges for NHS hospitals during covid-19 epidemic Comprehensive analysis of drugs to treat SARS-CoV-2 infection: mechanistic insights into current COVID-19 therapies Highly Active Antiretroviral Therapy (HAART) The end of AIDS: HIV infection as a chronic disease Investigating different mechanisms of action in combination therapy for influenza Artificial intelligence in COVID-19 drug repurposing The time to offer treatments for COVID-19 RAPID-C19. 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