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, Abdel G. Babiker, Jason V. Baker, Christina E. Barkauskas, Samuel M. Brown, Christina C. Chang, Victoria J. Davey, Annetine C. Gelijns, Adit A. Ginde, Birgit Grund, Elizabeth Higgs, Fleur Hudson, Virginia L. Kan, H. Clifford Lane, Thomas A. Murray, Roger Paredes, Mahesh K.B. Parmar, Sarah Pett, Andrew N. Phillips, Mark N. PolizzottoCavan Reilly, Uriel Sandkovsky, Shweta Sharma, Marc Teitelbaum, B. Taylor Thompson, Barnaby E. Young, James D. Neaton, Jens D. Lundgren

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)52-61
Number of pages10
JournalClinical Trials
Issue number1
StatePublished - Feb 2022

Bibliographical note

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: TICO is funded primarily through Operation Warp Speed (now Countermeasure Acceleration Group) as a sub-contract through the Leidos Biomedical Research, Inc. Additional funding was provided by the NIH (including NHLBI and NIAID), the US Department of Veterans Affairs, as well as the governments of Denmark (National Research Foundation; grant no. 126), Australia (National Health and Medical Research Council), Singapore (Singapore National Medical Research Council; COVID19RF-0005) and the United Kingdom (Medical Research Council, MRC_UU_12023/23).

Publisher Copyright:
© The Author(s) 2021.


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

PubMed: MeSH publication types

  • Clinical Trial Protocol
  • Journal Article
  • Research Support, Non-U.S. Gov't


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