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)
Por:
Murray, DD, Babiker, AG, Baker, JV, Barkauskas, CE, Brown, SM, Chang, CC, Davey, VJ, Gelijns, AC, Ginde, AA, Grund, B, Higgs, E, Hudson, F, Kan, VL, Lane, HC, Murray, TA, Paredes, R, Parmar, MKB, Pett, S, Phillips, AN, Polizzotto, MN, Reilly, C, Sandkovsky, U, Sharma, S, Teitelbaum, M, Thompson, BT, Young, BE, Neaton, JD and Lundgren, JD
Publicada:
1 feb 2022
Ahead of Print:
1 oct 2021
Resumen:
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.
Filiaciones:
Murray, DD:
Rigshosp, CHIP Ctr Excellence Hlth Immun & Infect, Dept Infect Dis, DK-2100 Copenhagen, Denmark
Babiker, AG:
UCL, Med Res Council Clin Trials Unit UCL, Inst Clin Trials & Methodol, London, England
Baker, JV:
Hennepin Healthcare Res Inst, Minneapolis, MN USA
Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA
Barkauskas, CE:
Duke Univ, Dept Med, Div Pulm Allergy & Crit Care Med, Durham, NC USA
Brown, SM:
Intermt Med Ctr, Murray, UT USA
Univ Utah, Sch Med, Salt Lake City, UT USA
Chang, CC:
Univ New South Wales, Kirby Inst, Sydney, NSW, Australia
Davey, VJ:
US Dept Vet Affairs, Washington, DC USA
Gelijns, AC:
Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA
Ginde, AA:
Univ Colorado, Dept Emergency Med, Sch Med, Aurora, CO USA
Grund, B:
Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA
Higgs, E:
NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA
Hudson, F:
UCL, Med Res Council Clin Trials Unit UCL, Inst Clin Trials & Methodol, London, England
Kan, VL:
Vet Affairs Med Ctr, 50 Irving St NW, Washington, DC 20422 USA
George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA
Lane, HC:
NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA
Murray, TA:
Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA
:
Hosp Univ Germans Trias I Pujol, Infect Dis Dept, Catalonia, Spain
Hosp Univ Germans Trias I Pujol, IrsiCaixa Aids Res Inst, Catalonia, Spain
Parmar, MKB:
UCL, Med Res Council Clin Trials Unit UCL, Inst Clin Trials & Methodol, London, England
Pett, S:
UCL, Med Res Council Clin Trials Unit UCL, Inst Clin Trials & Methodol, London, England
UCL, Inst Global Hlth, London, England
Phillips, AN:
Rigshosp, CHIP Ctr Excellence Hlth Immun & Infect, Dept Infect Dis, DK-2100 Copenhagen, Denmark
UCL, Inst Global Hlth, London, England
Polizzotto, MN:
Univ New South Wales, Kirby Inst, Sydney, NSW, Australia
St Vincents Hosp, Sydney, NSW, Australia
Reilly, C:
Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA
Sandkovsky, U:
Baylor Univ, Med Ctr, Div Infect Dis, Dallas, TX USA
Sharma, S:
Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA
Teitelbaum, M:
Leidos Biomed Res Inc, Frederick, MD USA
Thompson, BT:
Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care, Boston, MA 02114 USA
Harvard Med Sch, Boston, MA 02115 USA
Young, BE:
Natl Ctr Infect Dis, Singapore, Singapore
Tan Tock Seng Hosp, Singapore, Singapore
Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore
Neaton, JD:
Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA
Lundgren, JD:
Rigshosp, CHIP Ctr Excellence Hlth Immun & Infect, Dept Infect Dis, DK-2100 Copenhagen, Denmark
Green Submitted, Green Accepted, Bronze
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