BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Barts Cardiac Centre University College London London UK

Belfast Heart Centre Royal Victoria Hospital Belfast UK

Cardiac Imaging Department Barts Heart Centre London UK

Centre for Paediatric and Adolescent Medicine University Medical Centre University of Mainz Mainz Germany

Clinical Trials Unit Haukeland University Hospital Bergen Norway

Departamento de Ciencias Biológicas CONICET Facultad de Ciencias Exactas IIFP Universidad Nacional de La Plata La Plata Argentina

Department of Cardiovascular Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Clinical Medicine University of Bergen and Haukeland University Hospital Bergen Norway

Department of Endocrinology and Clinical Nutrition University Hospital Zurich and University of Zurich Zurich Switzerland

Department of Endocrinology and Metabolic Medicine Salford Royal NHS Foundation Trust Salford UK

Department of Endocrinology and Metabolism Academic Medical Centre University of Amsterdam Amsterdam The Netherlands

Department of Internal Medicine Université Paris 7 Hôpital Bichat Claude Bernard Paris France

Department of Medical Biochemistry and Immunology University Hospital of Wales Cardiff Wales UK

Department of Nephrology Royal Melbourne Hospital Melbourne Victoria Australia

Department of Nephrology Royal Perth Hospital Perth Western Australia Australia

Department of Paediatrics University of Minnesota Minneapolis MN United States

Division of Medical Genetics Department of Pediatrics Faculty of Medicine and Health Sciences Université de Sherbrooke Sherbrooke Canada

Division of Nephrology Belcolle Hospital Viterbo Italy

Division of Nephrology University of Alabama at Birmingham Birmingham AL USA

Fundación Jiménez Díaz Área de Patología Cardiovascular Renal e Hipertensión Madrid Spain

Fundation for the Study of Neurometabolic Diseases FESEN Argentina

Genetics and Molecular Pathology SA Pathology Women's and Children's Hospital North Adelaide Australia

Inborn Errors of Metabolism Reference Centre North Lisbon Hospital Centre Lisbon Portugal

Institute of Human Genetics University Medical Centre University of Mainz Mainz Germany

Institute of Metabolic Disease Baylor Research Institute Dallas TX USA

Lysosomal Storage Disorders Unit Royal Free Hospital NHS Foundation Trust and University College London London UK

Medical Endocrinology and Metabolism Rigshospitalet Copenhagen Denmark

Medical Genetics Service HCPA Department of Genetics UFRGS Porto Alegre Rio Grande do Sul Brazil

Medicine Dalhousie University Halifax Nova Scotia Canada

Neurological Unit St Bassiano Hospital Bassano del Grappa Italy

Rare and Metabolic Diseases Unit Vall Hebron University Hospital Universitat Autònoma de Barcelona Barcelona Spain

Service of Medical Genetics São João University Hospital Centre Alameda Hernãni Monteiro Porto Portugal

Unité de Recherche Clinique Centre de Recherche et Service de Néphrologie Hôpital du Sacré Coeur de Montreal Montreal Quebec Canada

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