Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: Findings from the opinion-based PREDICT-FD modified Delphi consensus initiative

Derralynn A. Hughes; Patricio Aguiar; Patrick B. Deegan; Fatih Ezgu; Andrea Frustaci; Olivier Lidove; Aleš Linhart; Jean Claude Lubanda; James C. Moon; Kathleen Nicholls; Dau Ming Niu; Albina Nowak; Uma Ramaswami; Ricardo Reisin; Paula Rozenfeld; Raphael Schiffmann; Einar Svarstad; Mark Thomas; Roser Torra; Bojan Vujkovac; David G. Warnock; Michael L. West; Jack Johnson; Mark J. Rolfe; Sandro Feriozzi

doi:10.1136/bmjopen-2019-035182

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: Findings from the opinion-based PREDICT-FD modified Delphi consensus initiative

Derralynn A. Hughes, Patricio Aguiar, Patrick B. Deegan, Fatih Ezgu, Andrea Frustaci, Olivier Lidove, Aleš Linhart, Jean Claude Lubanda, James C. Moon, Kathleen Nicholls, Dau Ming Niu, Albina Nowak, Uma Ramaswami, Ricardo Reisin, Paula Rozenfeld, Raphael Schiffmann, Einar Svarstad, Mark Thomas, Roser Torra, Bojan VujkovacDavid G. Warnock, Michael L. West, Jack Johnson, Mark J. Rolfe, Sandro Feriozzi

Medicine

Résultat de recherche: Article › examen par les pairs

28 Citations (Scopus)

Résumé

Objectives The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. Design and setting Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-Text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. Results A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. Conclusions PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.

Langue d'origine	English
Numéro d'article	e035182
Journal	BMJ Open
Volume	10
Numéro de publication	10
DOI	https://doi.org/10.1136/bmjopen-2019-035182
Statut de publication	Published - oct. 10 2020

Note bibliographique

Funding Information:
Funding Administration and coordination of the PREDICT-FD initiative and medical writing support were funded by an unrestricted independent educational grant (IME-GBR-15474) from Shire International GmbH, Zug, Switzerland, now part of Takeda Pharmaceutical Company. Shire/Takeda was not involved in the planning, design or delivery of the initiative. No reimbursement or funding was offered to the voting panel, to the cochairs or to any other organisation participating in the initiative.

Funding Information:
Competing interests DAH: advisory boards for Amicus, Sanofi, Shire (now part of Takeda); consulting fees from Amicus, Idorsia, Sanofi and Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda). PA: research grant and honoraria from Shire (now part of Takeda); honoraria from Amicus, Biomarin, Sanofi and Ultragenyx. PBD: speaker honoraria from and advisory boards for Takeda and Sanofi; consultancy for Sanofi. FE: travel grants and speaker honoraria from Pfizer, Sanofi Genzyme and Takeda. AF: research grants from Amicus and Shire. OL: travel grants and speaker honoraria from Amicus, Sanofi Genzyme and Shire HGT. AL: speaker’s honoraria or consultation fees from Amicus, Sanofi Genzyme and Takeda. J-CL: speaker’s honoraria and consultation fees from Shire. JCM: research grant and speaker honoraria from Sanofi Genzyme; advisory board for, and honoraria from ST; consulting fees from 4DMT. KN: research support and/or honoraria from Amicus, Idorsia, Protalix, Sanofi and Shire (now part of Takeda); advisory boards for Amicus, Sanofi and Shire (now part of Takeda). D-MN: research funding from Shire (now part of Takeda) and Sanofi. AN: honoraria and research support from Sanofi Genzyme and Shire (now part of Takeda). UR: advisory boards for Amicus, Chiesi, Idorsia and Shire; travel grants and honoraria from Amicus, Genzyme and Shire. RR: travel grants and speaker honoraria from Amicus and Shire HGT (now part of Takeda). PR: advisory board, consulting fees and research grant from Shire (now part of Takeda). RS: advisory boards for Amicus, Sanofi, Shire (now part of Takeda); honoraria from Amicus and Shire; research funding from Idorisia, Protalix, Sanofi Genzyme and Takeda. ES: speaker’s fees and travel support from Amicus, Sanofi Genzyme and Shire; advisory board honoraria from Amicus and Sanofi Genzyme. MT: advisory boards for Amicus, Sanofi and Shire (now part of Takeda); travel grants and speaker’s honoraria from Amicus, Sanofi and Shire; research funding from Amicus, AVROBIO and Idorsia. RT: travel grants, speaker’s honoraria or consultation fees from Amicus, Sanofi Genzyme and Takeda. BV: speaker’s fees and travel support from Greenovation, Sanofi Genzyme and Shire/Takeda; advisory board honoraria from Sanofi Genzyme. DGW: advisory boards for Amicus, Avrobio, Freeline Therapeutics, 4D-MT Technology, Idorsia and Protalix; honoraria and travel expenses from Amicus, Protalix and Sanofi; and equity interest in Reata Pharmaceuticals. MLW: advisory boards for Amicus, Sanofi and Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire; research funding from Amicus, Idorisia, Protalix and Shire. JJ: honoraria from Sanofi; travel expenses from Amicus and Sanofi. MJR is an employee of Oxford PharmaGenesis (Oxford, UK). SF: advisory boards for Amicus; consulting fees from Shire (now part of Takeda); contracted research from Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda); speaker’s bureau for Amicus, Sanofi and Shire (now part of Takeda); travel expenses from Amicus, Sanofi and Shire (now part of Takeda).

Funding Information:
4Medicine Department, University of Lisbon, Lisbon, Portugal 5Lysosomal Disorders Unit, Addenbrooke’s Hospital, Cambridge, UK 6Department of Medicine, University of Cambridge, Cambridge, UK 7Department and Laboratory of Paediatric Metabolic Disorders, Gazi University, Ankara, Turkey 8Department of Cardiovascular, Respiratory, Nephrologic, Geriatric and Anesthesiologic Sciences, University of Rome La Sapienza, Rome, Italy 9Department of Internal Medicine-Rheumatology, Croix Saint Simon Hospital, Paris, France 10Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic 11Cardiac Imaging Department, Barts Heart Centre, London, UK 12Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia 13Department of Medicine, The University of Melbourne - Parkville Campus, Melbourne, Victoria, Australia 14Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan 15Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 16Department of Endocrinology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland 17Department of Internal Medicine, Psychiatry University Hospital Zurich, Zurich, Switzerland 18Department of Neurology, British Hospital of Buenos Aires, Buenos Aires, Argentina 19Instituto de Estudios Inmunológicos y Fisiopatológicos, UNLP - CONICET, La Plata, Argentina 20Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA 21Department of Clinical Medicine, University of Bergen, Bergen, Norway 22Department of Medicine, Haukeland University Hospital, Bergen, Norway 23Department of Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia 24Inherited Renal Diseases Unit, Autonomous University of Barcelona, Barcelona, Spain 25Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia 26Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA 27Medicine, Dalhousie University, Halifax, Nova Scotia, Canada 28Fabry Support & Information Group, Concordia, Missouri, USA 29Fabry International Network, Beveren, Belgium 30Oxford PharmaGenesis, Oxford, UK 31Division of Nephrology, Belcolle Hospital, Viterbo, Italy Acknowledgements This initiative is endorsed by the Fabry International Network. The authors are grateful to Oxford PharmaGenesis, Oxford, UK, for providing administrative and project management support for the PREDICT-FD initiative and for medical writing, editorial support and project management support in preparation of this manuscript. This research and support from Oxford PharmaGenesis were funded by an unrestricted independent medical education grant (IME-GBR-15474) from Shire International (now part of Takeda Pharmaceutical Company), Zug, Switzerland. The authors chose independently to work with Oxford PharmaGenesis, without input from Shire International GmbH.

Publisher Copyright:
© 2020 Thieme Medical Publishers, Inc.. All rights reserved.

ASJC Scopus Subject Areas

General Medicine

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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10.1136/bmjopen-2019-035182

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Hughes, D. A., Aguiar, P., Deegan, P. B., Ezgu, F., Frustaci, A., Lidove, O., Linhart, A., Lubanda, J. C., Moon, J. C., Nicholls, K., Niu, D. M., Nowak, A., Ramaswami, U., Reisin, R., Rozenfeld, P., Schiffmann, R., Svarstad, E., Thomas, M., Torra, R., ... Feriozzi, S. (2020). Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: Findings from the opinion-based PREDICT-FD modified Delphi consensus initiative. BMJ Open, 10(10), Article e035182. https://doi.org/10.1136/bmjopen-2019-035182

Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: Findings from the opinion-based PREDICT-FD modified Delphi consensus initiative. / Hughes, Derralynn A.; Aguiar, Patricio; Deegan, Patrick B. et al.
Dans: BMJ Open, Vol. 10, N° 10, e035182, 10.10.2020.

Résultat de recherche: Article › examen par les pairs

Hughes, DA, Aguiar, P, Deegan, PB, Ezgu, F, Frustaci, A, Lidove, O, Linhart, A, Lubanda, JC, Moon, JC, Nicholls, K, Niu, DM, Nowak, A, Ramaswami, U, Reisin, R, Rozenfeld, P, Schiffmann, R, Svarstad, E, Thomas, M, Torra, R, Vujkovac, B, Warnock, DG, West, ML, Johnson, J, Rolfe, MJ & Feriozzi, S 2020, 'Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: Findings from the opinion-based PREDICT-FD modified Delphi consensus initiative', BMJ Open, vol. 10, n° 10, e035182. https://doi.org/10.1136/bmjopen-2019-035182

@article{4e11a7cd0528496792e2b9b38c7af71e,

title = "Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: Findings from the opinion-based PREDICT-FD modified Delphi consensus initiative",

abstract = "Objectives The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. Design and setting Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-Text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. Results A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. Conclusions PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised. ",

author = "Hughes, {Derralynn A.} and Patricio Aguiar and Deegan, {Patrick B.} and Fatih Ezgu and Andrea Frustaci and Olivier Lidove and Ale{\v s} Linhart and Lubanda, {Jean Claude} and Moon, {James C.} and Kathleen Nicholls and Niu, {Dau Ming} and Albina Nowak and Uma Ramaswami and Ricardo Reisin and Paula Rozenfeld and Raphael Schiffmann and Einar Svarstad and Mark Thomas and Roser Torra and Bojan Vujkovac and Warnock, {David G.} and West, {Michael L.} and Jack Johnson and Rolfe, {Mark J.} and Sandro Feriozzi",

note = "Funding Information: Funding Administration and coordination of the PREDICT-FD initiative and medical writing support were funded by an unrestricted independent educational grant (IME-GBR-15474) from Shire International GmbH, Zug, Switzerland, now part of Takeda Pharmaceutical Company. Shire/Takeda was not involved in the planning, design or delivery of the initiative. No reimbursement or funding was offered to the voting panel, to the cochairs or to any other organisation participating in the initiative. Funding Information: Competing interests DAH: advisory boards for Amicus, Sanofi, Shire (now part of Takeda); consulting fees from Amicus, Idorsia, Sanofi and Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda). PA: research grant and honoraria from Shire (now part of Takeda); honoraria from Amicus, Biomarin, Sanofi and Ultragenyx. PBD: speaker honoraria from and advisory boards for Takeda and Sanofi; consultancy for Sanofi. FE: travel grants and speaker honoraria from Pfizer, Sanofi Genzyme and Takeda. AF: research grants from Amicus and Shire. OL: travel grants and speaker honoraria from Amicus, Sanofi Genzyme and Shire HGT. AL: speaker{\textquoteright}s honoraria or consultation fees from Amicus, Sanofi Genzyme and Takeda. J-CL: speaker{\textquoteright}s honoraria and consultation fees from Shire. JCM: research grant and speaker honoraria from Sanofi Genzyme; advisory board for, and honoraria from ST; consulting fees from 4DMT. KN: research support and/or honoraria from Amicus, Idorsia, Protalix, Sanofi and Shire (now part of Takeda); advisory boards for Amicus, Sanofi and Shire (now part of Takeda). D-MN: research funding from Shire (now part of Takeda) and Sanofi. AN: honoraria and research support from Sanofi Genzyme and Shire (now part of Takeda). UR: advisory boards for Amicus, Chiesi, Idorsia and Shire; travel grants and honoraria from Amicus, Genzyme and Shire. RR: travel grants and speaker honoraria from Amicus and Shire HGT (now part of Takeda). PR: advisory board, consulting fees and research grant from Shire (now part of Takeda). RS: advisory boards for Amicus, Sanofi, Shire (now part of Takeda); honoraria from Amicus and Shire; research funding from Idorisia, Protalix, Sanofi Genzyme and Takeda. ES: speaker{\textquoteright}s fees and travel support from Amicus, Sanofi Genzyme and Shire; advisory board honoraria from Amicus and Sanofi Genzyme. MT: advisory boards for Amicus, Sanofi and Shire (now part of Takeda); travel grants and speaker{\textquoteright}s honoraria from Amicus, Sanofi and Shire; research funding from Amicus, AVROBIO and Idorsia. RT: travel grants, speaker{\textquoteright}s honoraria or consultation fees from Amicus, Sanofi Genzyme and Takeda. BV: speaker{\textquoteright}s fees and travel support from Greenovation, Sanofi Genzyme and Shire/Takeda; advisory board honoraria from Sanofi Genzyme. DGW: advisory boards for Amicus, Avrobio, Freeline Therapeutics, 4D-MT Technology, Idorsia and Protalix; honoraria and travel expenses from Amicus, Protalix and Sanofi; and equity interest in Reata Pharmaceuticals. MLW: advisory boards for Amicus, Sanofi and Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire; research funding from Amicus, Idorisia, Protalix and Shire. JJ: honoraria from Sanofi; travel expenses from Amicus and Sanofi. MJR is an employee of Oxford PharmaGenesis (Oxford, UK). SF: advisory boards for Amicus; consulting fees from Shire (now part of Takeda); contracted research from Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda); speaker{\textquoteright}s bureau for Amicus, Sanofi and Shire (now part of Takeda); travel expenses from Amicus, Sanofi and Shire (now part of Takeda). Funding Information: 4Medicine Department, University of Lisbon, Lisbon, Portugal 5Lysosomal Disorders Unit, Addenbrooke{\textquoteright}s Hospital, Cambridge, UK 6Department of Medicine, University of Cambridge, Cambridge, UK 7Department and Laboratory of Paediatric Metabolic Disorders, Gazi University, Ankara, Turkey 8Department of Cardiovascular, Respiratory, Nephrologic, Geriatric and Anesthesiologic Sciences, University of Rome La Sapienza, Rome, Italy 9Department of Internal Medicine-Rheumatology, Croix Saint Simon Hospital, Paris, France 10Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic 11Cardiac Imaging Department, Barts Heart Centre, London, UK 12Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia 13Department of Medicine, The University of Melbourne - Parkville Campus, Melbourne, Victoria, Australia 14Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan 15Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 16Department of Endocrinology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland 17Department of Internal Medicine, Psychiatry University Hospital Zurich, Zurich, Switzerland 18Department of Neurology, British Hospital of Buenos Aires, Buenos Aires, Argentina 19Instituto de Estudios Inmunol{\'o}gicos y Fisiopatol{\'o}gicos, UNLP - CONICET, La Plata, Argentina 20Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA 21Department of Clinical Medicine, University of Bergen, Bergen, Norway 22Department of Medicine, Haukeland University Hospital, Bergen, Norway 23Department of Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia 24Inherited Renal Diseases Unit, Autonomous University of Barcelona, Barcelona, Spain 25Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia 26Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA 27Medicine, Dalhousie University, Halifax, Nova Scotia, Canada 28Fabry Support & Information Group, Concordia, Missouri, USA 29Fabry International Network, Beveren, Belgium 30Oxford PharmaGenesis, Oxford, UK 31Division of Nephrology, Belcolle Hospital, Viterbo, Italy Acknowledgements This initiative is endorsed by the Fabry International Network. The authors are grateful to Oxford PharmaGenesis, Oxford, UK, for providing administrative and project management support for the PREDICT-FD initiative and for medical writing, editorial support and project management support in preparation of this manuscript. This research and support from Oxford PharmaGenesis were funded by an unrestricted independent medical education grant (IME-GBR-15474) from Shire International (now part of Takeda Pharmaceutical Company), Zug, Switzerland. The authors chose independently to work with Oxford PharmaGenesis, without input from Shire International GmbH. Publisher Copyright: {\textcopyright} 2020 Thieme Medical Publishers, Inc.. All rights reserved.",

year = "2020",

month = oct,

day = "10",

doi = "10.1136/bmjopen-2019-035182",

language = "English",

volume = "10",

journal = "BMJ Open",

issn = "2044-6055",

publisher = "BMJ Publishing Group",

number = "10",

}

TY - JOUR

T1 - Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation

T2 - Findings from the opinion-based PREDICT-FD modified Delphi consensus initiative

AU - Hughes, Derralynn A.

AU - Aguiar, Patricio

AU - Deegan, Patrick B.

AU - Ezgu, Fatih

AU - Frustaci, Andrea

AU - Lidove, Olivier

AU - Linhart, Aleš

AU - Lubanda, Jean Claude

AU - Moon, James C.

AU - Nicholls, Kathleen

AU - Niu, Dau Ming

AU - Nowak, Albina

AU - Ramaswami, Uma

AU - Reisin, Ricardo

AU - Rozenfeld, Paula

AU - Schiffmann, Raphael

AU - Svarstad, Einar

AU - Thomas, Mark

AU - Torra, Roser

AU - Vujkovac, Bojan

AU - Warnock, David G.

AU - West, Michael L.

AU - Johnson, Jack

AU - Rolfe, Mark J.

AU - Feriozzi, Sandro

N1 - Funding Information: Funding Administration and coordination of the PREDICT-FD initiative and medical writing support were funded by an unrestricted independent educational grant (IME-GBR-15474) from Shire International GmbH, Zug, Switzerland, now part of Takeda Pharmaceutical Company. Shire/Takeda was not involved in the planning, design or delivery of the initiative. No reimbursement or funding was offered to the voting panel, to the cochairs or to any other organisation participating in the initiative. Funding Information: Competing interests DAH: advisory boards for Amicus, Sanofi, Shire (now part of Takeda); consulting fees from Amicus, Idorsia, Sanofi and Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda). PA: research grant and honoraria from Shire (now part of Takeda); honoraria from Amicus, Biomarin, Sanofi and Ultragenyx. PBD: speaker honoraria from and advisory boards for Takeda and Sanofi; consultancy for Sanofi. FE: travel grants and speaker honoraria from Pfizer, Sanofi Genzyme and Takeda. AF: research grants from Amicus and Shire. OL: travel grants and speaker honoraria from Amicus, Sanofi Genzyme and Shire HGT. AL: speaker’s honoraria or consultation fees from Amicus, Sanofi Genzyme and Takeda. J-CL: speaker’s honoraria and consultation fees from Shire. JCM: research grant and speaker honoraria from Sanofi Genzyme; advisory board for, and honoraria from ST; consulting fees from 4DMT. KN: research support and/or honoraria from Amicus, Idorsia, Protalix, Sanofi and Shire (now part of Takeda); advisory boards for Amicus, Sanofi and Shire (now part of Takeda). D-MN: research funding from Shire (now part of Takeda) and Sanofi. AN: honoraria and research support from Sanofi Genzyme and Shire (now part of Takeda). UR: advisory boards for Amicus, Chiesi, Idorsia and Shire; travel grants and honoraria from Amicus, Genzyme and Shire. RR: travel grants and speaker honoraria from Amicus and Shire HGT (now part of Takeda). PR: advisory board, consulting fees and research grant from Shire (now part of Takeda). RS: advisory boards for Amicus, Sanofi, Shire (now part of Takeda); honoraria from Amicus and Shire; research funding from Idorisia, Protalix, Sanofi Genzyme and Takeda. ES: speaker’s fees and travel support from Amicus, Sanofi Genzyme and Shire; advisory board honoraria from Amicus and Sanofi Genzyme. MT: advisory boards for Amicus, Sanofi and Shire (now part of Takeda); travel grants and speaker’s honoraria from Amicus, Sanofi and Shire; research funding from Amicus, AVROBIO and Idorsia. RT: travel grants, speaker’s honoraria or consultation fees from Amicus, Sanofi Genzyme and Takeda. BV: speaker’s fees and travel support from Greenovation, Sanofi Genzyme and Shire/Takeda; advisory board honoraria from Sanofi Genzyme. DGW: advisory boards for Amicus, Avrobio, Freeline Therapeutics, 4D-MT Technology, Idorsia and Protalix; honoraria and travel expenses from Amicus, Protalix and Sanofi; and equity interest in Reata Pharmaceuticals. MLW: advisory boards for Amicus, Sanofi and Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire; research funding from Amicus, Idorisia, Protalix and Shire. JJ: honoraria from Sanofi; travel expenses from Amicus and Sanofi. MJR is an employee of Oxford PharmaGenesis (Oxford, UK). SF: advisory boards for Amicus; consulting fees from Shire (now part of Takeda); contracted research from Shire (now part of Takeda); honoraria from Amicus, Sanofi and Shire (now part of Takeda); speaker’s bureau for Amicus, Sanofi and Shire (now part of Takeda); travel expenses from Amicus, Sanofi and Shire (now part of Takeda). Funding Information: 4Medicine Department, University of Lisbon, Lisbon, Portugal 5Lysosomal Disorders Unit, Addenbrooke’s Hospital, Cambridge, UK 6Department of Medicine, University of Cambridge, Cambridge, UK 7Department and Laboratory of Paediatric Metabolic Disorders, Gazi University, Ankara, Turkey 8Department of Cardiovascular, Respiratory, Nephrologic, Geriatric and Anesthesiologic Sciences, University of Rome La Sapienza, Rome, Italy 9Department of Internal Medicine-Rheumatology, Croix Saint Simon Hospital, Paris, France 10Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic 11Cardiac Imaging Department, Barts Heart Centre, London, UK 12Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia 13Department of Medicine, The University of Melbourne - Parkville Campus, Melbourne, Victoria, Australia 14Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan 15Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 16Department of Endocrinology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland 17Department of Internal Medicine, Psychiatry University Hospital Zurich, Zurich, Switzerland 18Department of Neurology, British Hospital of Buenos Aires, Buenos Aires, Argentina 19Instituto de Estudios Inmunológicos y Fisiopatológicos, UNLP - CONICET, La Plata, Argentina 20Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA 21Department of Clinical Medicine, University of Bergen, Bergen, Norway 22Department of Medicine, Haukeland University Hospital, Bergen, Norway 23Department of Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia 24Inherited Renal Diseases Unit, Autonomous University of Barcelona, Barcelona, Spain 25Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia 26Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama, USA 27Medicine, Dalhousie University, Halifax, Nova Scotia, Canada 28Fabry Support & Information Group, Concordia, Missouri, USA 29Fabry International Network, Beveren, Belgium 30Oxford PharmaGenesis, Oxford, UK 31Division of Nephrology, Belcolle Hospital, Viterbo, Italy Acknowledgements This initiative is endorsed by the Fabry International Network. The authors are grateful to Oxford PharmaGenesis, Oxford, UK, for providing administrative and project management support for the PREDICT-FD initiative and for medical writing, editorial support and project management support in preparation of this manuscript. This research and support from Oxford PharmaGenesis were funded by an unrestricted independent medical education grant (IME-GBR-15474) from Shire International (now part of Takeda Pharmaceutical Company), Zug, Switzerland. The authors chose independently to work with Oxford PharmaGenesis, without input from Shire International GmbH. Publisher Copyright: © 2020 Thieme Medical Publishers, Inc.. All rights reserved.

PY - 2020/10/10

Y1 - 2020/10/10

N2 - Objectives The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. Design and setting Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-Text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. Results A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. Conclusions PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.

AB - Objectives The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. Design and setting Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-Text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. Results A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. Conclusions PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.

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U2 - 10.1136/bmjopen-2019-035182

DO - 10.1136/bmjopen-2019-035182

M3 - Article

C2 - 33039984

AN - SCOPUS:85092752427

SN - 2044-6055

VL - 10

JO - BMJ Open

JF - BMJ Open

IS - 10

M1 - e035182

ER -