Design, Analysis, and Pitfalls of Clinical Trials Using Ex Situ Liver Machine Perfusion: The International Liver Transplantation Society Consensus Guidelines.
Martins PN., Rizzari MD., Ghinolfi D., Jochmans I., Attia M., Jalan R., Friend PJ., ILTS Special Interest Group “DCD, Preservation and Machine Perfusion”: None., Chair: None., MD, PhD, FAST, FEBS, FACS (Univ Massachusetts, United States) Vice-chair None., MD (Henry Ford Hospital, United States) None., Members: None., MD (Leeds, United Kingdom) None., MD, PhD (Pisa, Italy) None., MD, PhD (Leuven, Belgium) None., MBBS, MD, PhD, FRCP, FRCPE, FAASLD. University College London (United Kingdom) None., MD (Oxford, United Kingdom); None., Attendees of the smaller-subgroup workshop: None., Al Faisal University, Riyadh, Saudi Arabia; None., Medical University of Warsaw, Warsaw, Poland; None., and None., First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; None., and None., School of Medicine the University of Tennessee Health Science Center Memphis, TN; None., University of Turin Medical School Hospital, Turin, Italy; None., Fondazione IRCCS Ca’Granda, University of Milan Medical School Hospital, Milan, Italy; None., Colorado University, Denver-Co, United States; None., Biocruces Bizkaia Health Research Institute. Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao, Spain; None., and None., Medical University of Warsaw, Warsaw, Poland.; None., Organ Recovery Systems, Zaventem, Belgium.; None., University of Oxford, Oxford, England; None., Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; None., Invited Faculty (panel of experts): None., For a list of their biographie please go to: https://wp-ilts-media.s3.amazonaws.com/wp-content/uploads/2020/01/29161208/02-Final-ILTS-Venice-2020-Meet-The-Faculty.pdf; None., Faculty listed in alphabetic order of last name: None., MD, Hospital of the University of Pennsylvania, Philadelphia, PA; None., MD, MS, FRCSGen, MBBCh, Leeds Teaching Hospitals, Leeds, United Kingdom; None., MD, PhD, FACS, ASA, FRCS, FRCS, University Hospital Zurich, Zurich, Switzerland; None., MD, PhD, King’s College Hospital, London, United Kingdom; None., MD, Mayo Clinic, Jacksonville, Florida, FL; None., MD, PhD, University of Liege, Liege, Belgium; None., MD, Beaujon Hospital, Paris, France; None., MD, FEBS, University Hospital Zurich, Zurich, Switzerland; None., MD, University of Wisconsin School of Medicine and Public Health, Madison, WI; None., MD, PhD, Hospital Clínic, Barcelona, Spain; None., MD, PhD, Hospital Clinic University of Barcelona, Barcelona, Spain; None., MD, Cruces University Hospital, Bilbao, Spain; None., MD, PhD, Universita di Pisa, Pisa, Italy; None., MD, FACS, New Jersey Medical School, Newark, NJ; None., MD, PhD, Hospital of Sun Yat-sen University, Guangzhou, China; None., MD, FRCS, King’s College Hospital, London, United Kingdom; None., MD, University of Rochester Medical Center, Rochester, NY; None., MD, Hospital Clínic, Barcelona, Spain; None., MD, PhD, MBBS, FRCPE, FRCP, FAASZD, University College London, London, United Kingdom; None., MD, PhD, University Hospitals Leuven, Leuven, Belgium; None., MD, PhD, University Hospital Zurich, Zurich, Switzerland; None., MD, UT/Methodist Transplant Institute Memphis, Memphis, TX; None., MD, PhD, The University of Massachusetts Medical School, Worcester, MA; None., MD, PhD, Hospital Universitario Marques de Valdecilla, Santander, Spain; None., MD, The Queen Elizabeth Hospital, Birmingham, United Kingdom; None., BMBCh, MA, MRCS, University of Oxford, Oxford, United Kingdom; None., MD, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; None., MD, MSc, PhD, UZ Gasthuisberg, Leuven, Belgium; None., MD, PhD, Erasmus MC, Rotterdam, The Netherlands; None., MD, PhD, FEBS, University Medical Center Groningen, Groningen, The Netherlands; None., MD, Cleveland Clinic, Cleveland, OH; None., MD, Henry Ford Transplant Institute, Detroit, MI; None., MD, University Hospital Pitié-Salpetrière, Paris, France; None., MD, The Queen Elizabeth Hospital, Birmingham, United Kingdom.; None., MD, FACS, Mayo Clinic Florida.; None., MD, Cambridge University Hospitals, Cambridge, United Kingdom. None., ILTS Special Interest Group “DCD, Preservation and Machine Perfusion”: and Chair: and MD, PhD, FAST, FEBS, FACS (Univ Massachusetts, United States) Vice-chair and MD (Henry Ford Hospital, United States) and Members: and MD (Leeds, United Kingdom) and MD, PhD (Pisa, Italy) and MD, PhD (Leuven, Belgium) and MBBS, MD, PhD, FRCP, FRCPE, FAASLD. University College London (United Kingdom) and MD (Oxford, United Kingdom); and Attendees of the smaller-subgroup workshop: and Al Faisal University, Riyadh, Saudi Arabia; and Medical University of Warsaw, Warsaw, Poland; and and and The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; and and and School of Medicine the University of Tennessee Health Science Center Memphis, TN; and University of Turin Medical School Hospital, Turin, Italy; and Fondazione IRCCS Ca’Granda, University of Milan Medical School Hospital, Milan, Italy; and Colorado University, Denver-Co, United States; and Biocruces Bizkaia Health Research Institute. Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao, Spain; and and and Medical University of Warsaw, Warsaw, Poland.; and Organ Recovery Systems, Zaventem, Belgium.; and University of Oxford, Oxford, England; and Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; and Invited Faculty (panel of experts): and For a list of their biographie please go to: https://wp-ilts-media.s3.amazonaws.com/wp-content/uploads/2020/01/29161208/02-Final-ILTS-Venice-2020-Meet-The-Faculty.pdf; and Faculty listed in alphabetic order of last name: and MD, Hospital of the University of Pennsylvania, Philadelphia, PA; and MD, MS, FRCSGen, MBBCh, Leeds Teaching Hospitals, Leeds, United Kingdom; and MD, PhD, FACS, ASA, FRCS, FRCS, University Hospital Zurich, Zurich, Switzerland; and MD, PhD, King’s College Hospital, London, United Kingdom; and MD, Mayo Clinic, Jacksonville, Florida, FL; and MD, PhD, University of Liege, Liege, Belgium; and MD, Beaujon Hospital, Paris, France; and MD, FEBS, University Hospital Zurich, Zurich, Switzerland; and MD, University of Wisconsin School of Medicine and Public Health, Madison, WI; and MD, PhD, Hospital Clínic, Barcelona, Spain; and MD, PhD, Hospital Clinic University of Barcelona, Barcelona, Spain; and MD, Cruces University Hospital, Bilbao, Spain; and MD, PhD, Universita di Pisa, Pisa, Italy; and MD, FACS, New Jersey Medical School, Newark, NJ; and MD, PhD, Hospital of Sun Yat-sen University, Guangzhou, China; and MD, FRCS, King’s College Hospital, London, United Kingdom; and MD, University of Rochester Medical Center, Rochester, NY; and MD, Hospital Clínic, Barcelona, Spain; and MD, PhD, MBBS, FRCPE, FRCP, FAASZD, University College London, London, United Kingdom; and MD, PhD, University Hospitals Leuven, Leuven, Belgium; and MD, PhD, University Hospital Zurich, Zurich, Switzerland; and MD, UT/Methodist Transplant Institute Memphis, Memphis, TX; and MD, PhD, The University of Massachusetts Medical School, Worcester, MA; and MD, PhD, Hospital Universitario Marques de Valdecilla, Santander, Spain; and MD, The Queen Elizabeth Hospital, Birmingham, United Kingdom; and BMBCh, MA, MRCS, University of Oxford, Oxford, United Kingdom; and MD, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; and MD, MSc, PhD, UZ Gasthuisberg, Leuven, Belgium; and MD, PhD, Erasmus MC, Rotterdam, The Netherlands; and MD, PhD, FEBS, University Medical Center Groningen, Groningen, The Netherlands; and MD, Cleveland Clinic, Cleveland, OH; and MD, Henry Ford Transplant Institute, Detroit, MI; and MD, University Hospital Pitié-Salpetrière, Paris, France; and MD, The Queen Elizabeth Hospital, Birmingham, United Kingdom.; and MD, FACS, Mayo Clinic Florida.; and MD, Cambridge University Hospitals, Cambridge, United Kingdom. None.
BACKGROUND: Recent trials in liver machine perfusion (MP) have revealed unique challenges beyond those seen in most clinical studies. Correct trial design and interpretation of data are essential to avoid drawing conclusions that may compromise patient safety and increase costs. METHODS: The International Liver Transplantation Society, through the Special Interest Group "DCD, Preservation and Machine Perfusion," established a working group to write consensus statements and guidelines on how future clinical trials in liver perfusion should be designed, with particular focus on relevant clinical endpoints and how different techniques of liver perfusion should be compared. Protocols, abstracts, and full published papers of clinical trials using liver MP were reviewed. The use of a simplified Grading of Recommendations Assessment, Development, and Evaluation working group (GRADE) system was attempted to assess the level of evidence. The working group presented its conclusions at the International Liver Transplantation Society consensus conference "DCD, Liver Preservation, and Machine Perfusion" held in Venice, Italy, on January 31, 2020. RESULTS: Twelve recommendations were proposed with the main conclusions that clinical trials investigating the effect of MP in liver transplantation should (1) make the protocol publicly available before the start of the trial, (2) be adequately powered, and (3) carefully consider timing of randomization in function of the primary outcome. CONCLUSIONS: There are issues with using accepted primary outcomes of liver transplantation trials in the context of MP trials, and no ideal endpoint could be defined by the working group. The setup of an international registry was considered vital by the working group.