Design and implementation of an international, multi-arm, multi-stage platform master protocol for trials of novel SARS-CoV-2 antiviral agents: Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3)

Daniel D. Murray, CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
Abdel G. Babiker, Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
Jason V. Baker, Hennepin Healthcare Research Institute, Minneapolis, MN, USA.
Christina E. Barkauskas, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC, USA.
Samuel M. Brown, Intermountain Medical Center, Murray, UT, USA.
Christina C. Chang, The Kirby Institute, University of New South Wales Sydney, Sydney, NSW, Australia.
Victoria J. Davey, U.S. Department of Veterans Affairs, Washington, DC, USA.
Annetine C. Gelijns, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Adit A. Ginde, Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Birgit Grund, Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Elizabeth Higgs, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Fleur Hudson, Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
Virginia L. Kan, Veteran Affairs Medical Center, Washington, DC, USA.
H Clifford Lane, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Thomas A. Murray, Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Roger Paredes, Infectious Diseases Department & IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Catalonia, Spain.
Mahesh Kb Parmar, Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
Sarah Pett, Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
Andrew N. Phillips, CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.
Mark N. Polizzotto, The Kirby Institute, University of New South Wales Sydney, Sydney, NSW, Australia.
Cavan Reilly, Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Uriel Sandkovsky, Division of Infectious Diseases, Baylor University Medical Center, Dallas, TX, USA.
Shweta Sharma, Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Marc Teitelbaum, Leidos Biomedical Research, Inc., Frederick, MD, USA.
B Taylor Thompson, Division of Pulmonary and Critical Care, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Barnaby E. Young, National Centre for Infectious Diseases, Singapore.
James D. Neaton, Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Jens D. Lundgren, CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark.

Document Type

Journal Article

Publication Date

2-1-2022

Journal

Clinical trials (London, England)

Volume

19

Issue

1

DOI

10.1177/17407745211049829

Keywords

COVID-19; SARS-CoV-2; multi-arm multi-stage; platform trials

Abstract

BACKGROUND/AIMS: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. METHODS: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. RESULTS: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.

Department

Medicine

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