Trial of Deferiprone in Parkinson's Disease.

N Engl J Med

From the Departments of Medical Pharmacology (D. Devos, A.-S.R., R.B., J.-C.D.), Neuroradiology (R.V., G.K., R.L., J.-P.P.), and Neurology (L.D., C.M.), University of Lille, Lille Neuroscience and Cognition, Team DVCD, INSERM Unité Mixte de Recherche Scientifique (UMRS) 1172, Centre Hospitalier Universitaire (CHU) de Lille, Expert Center of Parkinson's Disease, Lille Center of Excellence for Neurodegenerative Disorders (LiCEND) Network of Centers of Excellence in Neurodegeneration (CoEN) Center, NS-Park/FCRIN network, the Department of Biostatistics, University of Lille, CHU de Lille (J.L., A.D.), CHU de Lille, Direction de la Recherche et de l'Innovation (P.G.D., T.O., C.P., C.L.) and Vigilance des Essais Cliniques and Service de Pharmacologie (T.O., C.P., C.L.), CHU de Lille, Laboratoire de Biochimie-Hormonologie, Centre de Biologie Pathologie (P.P.), the University of Lille, CHU de Lille, Institut Pasteur de Lille, ULR4483-Impact de l'Environnement Chimique sur la Santé Humaine (G.G., O.S., J.C.), and the University of Lille, INSERM, CHU de Lille, Unité 1172-Degenerative and Vascular Cognitive Disorders (D. Deplanque), Lille, Clinical Investigation Center 1436, Departments of Neurosciences and Clinical Pharmacology, NS-Park/FCRIN network and NeuroToul CoEN Center, University Hospital of Toulouse, INSERM, University of Toulouse 3, Toulouse (O.R., F.O.-M.), Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP), INSERM, Centre National de la Recherche Scientifique (CNRS), Paris Brain Institute-Institut du Cerveau et de la Moelle Épinière (ICM), Department of Neurology, Centre d'Investigation Clinique Neurosciences, Hôpital Pitié-Salpêtrière (J.-C.C.), Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, and AP-HP, Hôpital Pitié-Salpêtrière, Department of Nuclear Medicine (M.-O.H.), Centre pour l'Acquisition et le Traitement des Images, US52-UAR2031, Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), ICM, Sorbonne Université, CNRS, INSERM, AP-HP (M.-O.H., J.-F.M., M.C.), Paris Brain Institute-ICM, Center for Neuroimaging Research, Sorbonne Université, INSERM Unité 1127, CNRS 7225, Department of Neuroradiology, Hôpital Pitié-Salpêtrière, AP-HP (S.L.), and ICM, CNRS UMR 7725, INSERM, Unité 1127, Sorbonne Université (J.-F.M., M.C.), Paris, the Department of Neurology, NS-Park/FCRIN network, Strasbourg University Hospital, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg (C.T.), Assistance Publique-Hôpitaux de Marseille, Department of Neurology and Movement Disorders, Timone University Hospital and Institut de Neurosciences de la Timone, Unité Mixte de Recherche (UMR) 7289, CNRS-Aix Marseille Université, Marseille (A.E.), University of Lyon, CNRS, UMR 5229, Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie, Centre Expert Parkinson NS-Park/FCRIN network, Bron (S.T.), Université Clermont Auvergne, EA7280, Clermont-Ferrand University Hospital, Neurology Department, Clermont-Ferrand (A.-R.M.), CHU de Bordeaux, Service de Neurologie des Maladies Neurodégénératives, Institut des Maladies Neurodégénératives (IMN) Clinique, University of Bordeaux, CNRS, IMN, UMR 5293, Bordeaux (W.G.M.), and Université Paris-Saclay, CEA, CNRS, NeuroSpin, Baobab, Gif-sur-Yvette (J.-F.M., M.C.) - all in France; the Department of Neurology, Medical University Innsbruck, Innsbruck, Austria (W.P., K.S.); Parkinson's Disease and Movement Disorders Unit, Hospital Clínic de Barcelona-Institut d'Investigacions Biomèdiques August Pi I Sunyer-Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)-European Reference Network for Rare Neurological Diseases, Maria de Maeztu Excellence Center-Institut de Neurociències, Universitat de Barcelona (Y.C.), and the Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Department of Medicine, Sant Pau Biomedical Research Institute, and CIBERNED (J.K.), Barcelona, and the Movement Disorders Unit, Hospital Germans Trias i Pujol, Badalona (D.V.) - all in Spain; Clinical Ageing Research Unit, Newcastle University, Newcastle upon Tyne (N.P.), Addenbrooke's Hospital (P.W.) and the ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge Biomedical Campus (J.A.D.), Cambridge, and Parkinson's UK, London (D.T.D.) - all in the United Kingdom; the Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic (E.R., P.D.); Radboud University Medical Center, Donders Institute for Brain, Cognition, and Behavior, Department of Neurology, Nijmegen (B.P., B.R.B.), and Amsterdam UMC location University of Amsterdam, Department of Neurology, and Amsterdam Neuroscience, Neurodegeneration, Amsterdam (R.M.A.B.) - all in the Netherlands; the Department of Neurology, Christian Albrechts University Kiel, Kiel (D.B., W.M.), the Department of Neurology, University Clinic, Ulm (M.O.), the Department of Geriatric Medicine, University Duisburg-Essen, Essen (R.D.), Rostock University Medical Center, Department of Neurology, and the German Center for Neurodegenerative Diseases, Research Site Rostock, Rostock (U.W.), and University Hospital of the Saarland, Homburg (S.B.) - all in Germany; Centro de Investigação em Arquitetura, Urbanismo e Design, Faculdade de Arquitetura, Universidade de Lisboa (J.F.), and Hospital de Santa Maria (M.V.S.C.), Lisbon, the Department of Neurology, Hospital da Senhora da Oliveira, Guimarães (M.G.), Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga (M.G.), and Hopitais da Universidade de Coimbra, Department of Neurology, Coimbra (C.J.) - all in Portugal; the Department of Medicine, University of Otago, Christchurch Campus, and New Zealand Brain Research Institute - both in Christchurch, New Zealand (W.G.M.); the Department of Medical Sciences, Neurology, Uppsala University, Uppsala, Sweden (D.N.); Leslie Dan Faculty of Pharmacy, University of Toronto, ApoPharma, and Chiesi Canada - all in Toronto (C.F., M.S., F.T.); Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia (S.A., A.I.B., J.A.D.); and the Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel (I.C.).

Published: December 2022

AI Article Synopsis

Article Abstract

Background: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear.

Methods: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.

Results: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.

Conclusions: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

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http://dx.doi.org/10.1056/NEJMoa2209254DOI Listing

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