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Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial.
Clin Trials. 2020 10; 17(5):491-500.CT

Abstract

BACKGROUND

Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care.

METHODS

An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death.

CONCLUSION

Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.

Authors+Show Affiliations

Max Rady Faculty of Health Sciences, Max Rady College of Medicine, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.Peter Munk Cardiac Centre, University Health Network and University of Toronto, Toronto, ON, Canada. Toronto General Hospital Research Institute, Toronto, ON, Canada. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.Toronto General Hospital Research Institute, Toronto, ON, Canada. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada. Department of Medicine, Division of Respirology, University Health Network, Toronto, ON, Canada.Peter Munk Cardiac Centre, University Health Network and University of Toronto, Toronto, ON, Canada.Faculty of Health Sciences, University of Bristol, Bristol, UK.Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.Peter Munk Cardiac Centre, University Health Network and University of Toronto, Toronto, ON, Canada.Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada.Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada.Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University & Hamilton Health Sciences, Hamilton, ON, Canada.Clinical Practice Assessment Unit, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.Peter Munk Cardiac Centre, University Health Network and University of Toronto, Toronto, ON, Canada.Center for Clinical Epidemiology, Jewish General Hospital/Lady Davis Institute, Division of Internal Medicine, Department of Medicine, McGill University, Montreal, QC, Canada.Max Rady Faculty of Health Sciences, Max Rady College of Medicine, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.Department of Surgery, St Michael's Hospital and the University of Toronto, Toronto, ON, Canada.The University of British Columbia, Vancouver, BC, Canada.Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital and Departments of Medicine, Surgery, and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada. CHU de Québec - Université Laval Research Centre, Population Health and Optimal Health Practices Research Unit, Trauma-Emergency-Critical Care Medicine, Université Laval, Québec, QC, Canada.Berry Consultants, LLC, Austin, TX, USA.The Zena and Michael A. Wiener Cardiovascular Institute, Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Medical Research Unit on Clinical Epidemiology, Mexican Social Security Institute, Mexico City, Mexico.Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.Ozmosis Research Inc., Toronto, ON, Canada.Department of Clinical Research, SOCAR Research SA, Nyon, Switzerland. Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, London, England.Department of Clinical Research, SOCAR Research SA, Nyon, Switzerland.Max Rady Faculty of Health Sciences, Max Rady College of Medicine, Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada. Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32815416

Citation

Houston, Brett L., et al. "Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study Design and Methodology for an International, Adaptive Bayesian Randomized Controlled Trial." Clinical Trials (London, England), vol. 17, no. 5, 2020, pp. 491-500.
Houston BL, Lawler PR, Goligher EC, et al. Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial. Clin Trials. 2020;17(5):491-500.
Houston, B. L., Lawler, P. R., Goligher, E. C., Farkouh, M. E., Bradbury, C., Carrier, M., Dzavik, V., Fergusson, D. A., Fowler, R. A., Galanaud, J. P., Gross, P. L., McDonald, E. G., Husain, M., Kahn, S. R., Kumar, A., Marshall, J., Murthy, S., Slutsky, A. S., Turgeon, A. F., ... Zarychanski, R. (2020). Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial. Clinical Trials (London, England), 17(5), 491-500. https://doi.org/10.1177/1740774520943846
Houston BL, et al. Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study Design and Methodology for an International, Adaptive Bayesian Randomized Controlled Trial. Clin Trials. 2020;17(5):491-500. PubMed PMID: 32815416.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial. AU - Houston,Brett L, AU - Lawler,Patrick R, AU - Goligher,Ewan C, AU - Farkouh,Michael E, AU - Bradbury,Charlotte, AU - Carrier,Marc, AU - Dzavik,Vlad, AU - Fergusson,Dean A, AU - Fowler,Robert A, AU - Galanaud,Jean-Phillippe, AU - Gross,Peter L, AU - McDonald,Emily G, AU - Husain,Mansoor, AU - Kahn,Susan R, AU - Kumar,Anand, AU - Marshall,John, AU - Murthy,Srinivas, AU - Slutsky,Arthur S, AU - Turgeon,Alexis F, AU - Berry,Scott M, AU - Rosenson,Robert S, AU - Escobedo,Jorge, AU - Nicolau,Jose C, AU - Bond,Lindsay, AU - Kirwan,Bridget-Anne, AU - de Brouwer,Sophie, AU - Zarychanski,Ryan, Y1 - 2020/08/20/ PY - 2020/8/21/pubmed PY - 2020/10/21/medline PY - 2020/8/21/entrez KW - COVID-19 KW - Heparin KW - adaptive clinical trial KW - protocol KW - thrombosis SP - 491 EP - 500 JF - Clinical trials (London, England) JO - Clin Trials VL - 17 IS - 5 N2 - BACKGROUND: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases. SN - 1740-7753 UR - https://www.unboundmedicine.com/medline/citation/32815416/Anti_Thrombotic_Therapy_to_Ameliorate_Complications_of_COVID_19__ATTACC_:_Study_design_and_methodology_for_an_international_adaptive_Bayesian_randomized_controlled_trial_ DB - PRIME DP - Unbound Medicine ER -