1921
Volume 103, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

As the global COVID-19 pandemic continues, unabated and clinical trials demonstrate limited effective pharmaceutical interventions, there is a pressing need to accelerate treatment evaluations. Among options for accelerated development is the evaluation of drug combinations in the absence of prior monotherapy data. This approach is appealing for a number of reasons. First, combining two or more drugs with related or complementary therapeutic effects permits a multipronged approach addressing the variable pathways of the disease. Second, if an individual component of a combination offers a therapeutic effect, then in the absence of antagonism, a trial of combination therapy should still detect individual efficacy. Third, this strategy is time saving. Rather than taking a stepwise approach to evaluating monotherapies, this strategy begins with testing all relevant therapeutic options. Finally, given the severity of the current pandemic and the absence of treatment options, the likelihood of detecting a treatment effect with combination therapy maintains scientific enthusiasm for evaluating repurposed treatments. Antiviral combination selection can be facilitated by insights regarding SARS-CoV-2 pathophysiology and cell cycle dynamics, supported by infectious disease and clinical pharmacology expert advice. We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Loading

Article metrics loading...

The graphs shown below represent data from March 2017
/content/journals/10.4269/ajtmh.20-0995
2020-08-21
2020-10-29
Loading full text...

Full text loading...

/deliver/fulltext/14761645/103/4/tpmd200995.html?itemId=/content/journals/10.4269/ajtmh.20-0995&mimeType=html&fmt=ahah

References

  1. Thorlund K, Dron L, Park J, Hsu G, Forrest JI, Mills EJ, 2020. A real-time dashboard of clinical trials for COVID-19. Lancet Digit Health 2: e286e287.
    [Google Scholar]
  2. Guy RK, DiPaola RS, Romanelli F, Dutch RE, 2020. Rapid repurposing of drugs for COVID-19. Science 368: 829830.
    [Google Scholar]
  3. Riva L et al., 2020. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature (Epub ahead of print 2020 Jul 24]. Available at: https://doi.org/10.1038/s41586-020-2577-1.
    [Google Scholar]
  4. Dodds MG, Krishna R, Goncalves A, Rayner CR, 2020. Model-informed drug repurposing: viral kinetic modelling to prioritize rational drug combinations for COVID-19. Br J Clin Pharmacol (Epub ahead of print 2020 Jul 21). Available at: https://doi.org/10.1111/bcp.14486.
    [Google Scholar]
  5. RECOVERY Collaborative Group, Horby P, Lim WS, et al., 2020. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med (Epub ahead of print 2020 Jul 17). Available at: https://doi.org/10.1056/NEJMoa2021436.
    [Google Scholar]
  6. Beigel JH et al., 2020. Remdesivir for the treatment of COVID-19---preliminary report. N Engl J Med (Epub ahead of print 2020 May 22). Available at: https://doi.org/10.1056/NEJMoa2007764.
    [Google Scholar]
  7. Hung IF et al., 2020. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 395: 16951704.
    [Google Scholar]
  8. The RECOVERY Trial, 2020. No Clinical Benefit from Use of Lopinavir-Ritonavir in Hospitalised COVID-19 Patients Studied in RECOVERY. Available at: https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-hospitalised-covid-19-patients-studied-in-recovery. Accessed August 7, 2020.
    [Google Scholar]
  9. United States Food Drug Administration, 2013. Guidance for Industry: Codevelopment of Two or More New Investigational Drugs for Use in Combination. Available at: https://www.fda.gov/media/80100/download. Accessed August 7, 2020.
    [Google Scholar]
  10. The Adaptive Platform Trials Coalition, 2019. Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov 18: 797807.
    [Google Scholar]
  11. Park JJH, Harari O, Dron L, Lester RT, Thorlund K, Mills EJ, 2020. An overview of platform trials with a checklist for clinical readers. J Clin Epidemiol 125: 18.
    [Google Scholar]
  12. Bhatt DL, Mehta C, 2016. Adaptive designs for clinical trials. N Engl J Med 375: 6574.
    [Google Scholar]
  13. World Health Organization, 2020. “Solidarity” Clinical Trial for COVID-19 Treatments. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments. Accessed August 7, 2020.
    [Google Scholar]
  14. Angus DC et al., 2020. The randomized embedded multifactorial adaptive platform for community-acquired pneumonia (REMAP-CAP) study: rationale and design. Ann Am Thorac Soc 17: 879891.
    [Google Scholar]
  15. Morita M, Suyama H, Igishi T, Shigeoka Y, Kodani M, Hashimoto K, Takeda K, Sumikawa T, Eiji S, 2007. Dexamethasone inhibits paclitaxel-induced cytotoxic activity through retinoblastoma protein dephosphorylation in non-small cell lung cancer cells. Int J Oncol 30: 187192.
    [Google Scholar]
  16. Havlir DV, Tierney C, Friedland GH, Pollard RB, Smeaton L, Sommadossi JP, Fox L, Kessler H, Fife KH, Richman DD, 2000. In vivo antagonism with zidovudine plus stavudine combination therapy. J Infect Dis 182: 321325.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journals/10.4269/ajtmh.20-0995
Loading
/content/journals/10.4269/ajtmh.20-0995
Loading

Data & Media loading...

  • Received : 11 Aug 2020
  • Accepted : 14 Aug 2020
  • Published online : 21 Aug 2020
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error