The Anti-Coronavirus Therapies (ACT) Trials: Design, Baseline Characteristics, and Challenges
John Eikelboom, MBBS, MSc,
Sumathy Rangarajan, MSc,
Sanjit S. Jolly, MD,
Emilie P. Belley-Cote, MD, PhD,
Richard Whitlock, MD, PhD,
Heather Beresh, MSc,
Gayle Lewis,
Lizhen Xu, PhD,
Noel Chan, MD,
Shrikant Bangdiwala, PhD,
Rafael Diaz, MD,
Andres Orlandini, MD,
Mohamed Hassany, MD,
Wadea M. Tarhuni, MD,
A.M. Yusufali, MD,
Sanjib Kumar Sharma, MD,
Anna Kontsevaya, PhD,
Patricio Lopez-Jaramillo, MD,
Alvaro Avezum, MD,
Antonio L. Dans, MD,
Sean Wasserman, MBChB,
Camilo Felix, MD,
Khawar Kazmi, MD,
Prem Pais, MD,
Denis Xavier, MD,
Renato D. Lopes, MD, PhD,
Otavio Berwanger, MD,
Menelas Nkeshimana, MMed,
William Harper, MD,
Mark Loeb, MD,
Shurjeel Choudhri, MD,
Michael E. Farkouh, MD,
Jackie Bosch, PhD,
Sonia S. Anand, PhD,
Salim Yusuf, DPhil
Affiliations
John Eikelboom, MBBS, MSc
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Corresponding author: John Eikelboom, Population Health Research Institute, 237 Barton St East, Hamilton, Ontario L9K 1H8, Canada. Tel.: +1-905-527-4322, x40323; fax: +1-905-521-1551.
Sumathy Rangarajan, MSc
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
Sanjit S. Jolly, MD
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Emilie P. Belley-Cote, MD, PhD
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Richard Whitlock, MD, PhD
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
Heather Beresh, MSc
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
Gayle Lewis
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
Lizhen Xu, PhD
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
Noel Chan, MD
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Shrikant Bangdiwala, PhD
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Rafael Diaz, MD
ECLA (Estudios Clínicos Latino America), ICR (Instituto Cardiovascular de Rosario), Rosario, Argentina
Andres Orlandini, MD
ECLA (Estudios Clínicos Latino America), ICR (Instituto Cardiovascular de Rosario), Rosario, Argentina
Mohamed Hassany, MD
National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
Wadea M. Tarhuni, MD
Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Department of Medicine, Western University, London, Ontario, Canada; Windsor Cardiac Centre, Windsor, Ontario, Canada
A.M. Yusufali, MD
Hatta Hospital, Dubai Medical College, Dubai Health Authority, Dubai, United Arab Emirates
Sanjib Kumar Sharma, MD
BP Koirala Institute of Health Sciences, Dharan, Nepal
Anna Kontsevaya, PhD
National Medical Research Centre for Therapy and Preventive Medicine, Moscow, Russian Federation
Patricio Lopez-Jaramillo, MD
Masira Research Institute, Medical School, Universidad de Santander, Bucaramanga, Colombia
Alvaro Avezum, MD
International Research Centre, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil
Antonio L. Dans, MD
University of the Philippines, Manila, Philippines
Sean Wasserman, MBChB
Wellcome Centre for Infectious Diseases Research in Africa, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Infectious Diseases and HIV Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
Camilo Felix, MD
Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
Khawar Kazmi, MD
National Institute of Cardiovascular Diseases, Rafique Shaheed Road, Karachi, Pakistan
Prem Pais, MD
St. John's Research Institute, Bangalore, India
Denis Xavier, MD
St. John’s Medical College and research Institute, Bangalore, India
Renato D. Lopes, MD, PhD
Division of Cardiology, Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina, USA; Global Cardiovascular Coalition, Alameda Campinas, São Paulo, Brazil
Otavio Berwanger, MD
Global Cardiovascular Coalition, Alameda Campinas, São Paulo, Brazil; Hospital Israelita Albert Einstein, São Paulo, Brazil
Menelas Nkeshimana, MMed
Centre Hospitalier Universitaire de Kigali, Kigali, Rwanda; Department of Internal Medicine, University of Rwanda, Kigali, Rwanda
William Harper, MD
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Mark Loeb, MD
Department of Pathology and Molecular Medicine, McMaster University. Hamilton, Ontario, Canada; Department of Health Evidence Methods, Evidence, and Impact, McMaster University. Hamilton, Ontario, Canada
Shurjeel Choudhri, MD
Medical & Scientific Affairs, Bayer Inc. Pharmaceuticals, Mississauga, Ontario, Canada
Michael E. Farkouh, MD
Peter Munk Cardiac Centre, University of Toronto, Toronto, Ontario, Canada
Jackie Bosch, PhD
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada
Sonia S. Anand, PhD
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Salim Yusuf, DPhil
Population Health Research Institute, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging. Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death. Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials. Résumé: Contexte: Il est urgent de mettre au point des traitements efficaces contre la COVID-19, mais il n’est pas facile de réaliser des essais à répartition aléatoire dans un contexte pandémique. Méthodologie: Les essais internationaux factoriels ACT (Anti-Coronavirus Therapy) avaient un objectif d’inscription de 3 500 patients externes et de 2 500 patients hospitalisés présentant une COVID-19 symptomatique. L’essai mené auprès de patients externes visait à évaluer la colchicine par rapport aux soins habituels, et l’aspirine par rapport aux soins habituels. Le paramètre d’évaluation principal au terme de la répartition aléatoire des patients était l’hospitalisation ou le décès dans le groupe traité par la colchicine, et la thrombose majeure, l’hospitalisation ou le décès dans le groupe traité par l’aspirine. L’essai mené auprès de patients hospitalisés visant à évaluer la colchicine par rapport aux soins habituels, et un traitement associant le rivaroxaban à 2,5 mg deux fois par jour et l’aspirine à 100 mg une fois par jour par rapport aux soins habituels. Le paramètre d’évaluation principal au terme de la répartition aléatoire des patients était le recours à l’oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par la colchicine, et la survenue de manifestations thrombotiques majeures, le recours à l’oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par l’association rivaroxaban-aspirine. Résultats: À la fin de la période d’inscription, le 10 février 2022, 3 917 patients externes et 2 611 patients hospitalisés formaient la population des essais. Certains aspects se sont révélés problématiques, notamment le manque de données préliminaires sur les interventions à évaluer, les incertitudes liées aux taux d’événements prévus, les retards touchant les approbations réglementaires et éthiques et les interventions de recherche, de même que l’évolution de la pandémie de COVID-19. Conclusions: Les essais ACT détermineront l’efficacité du traitement anti-inflammatoire par la colchicine et du traitement antithrombotique par l’aspirine, administrée seule ou en association avec le rivaroxaban, contre la COVID-19 légère, modérée ou sévère. Les leçons tirées de ces essais orienteront la planification d’essais ultérieurs.
