Trial of Deferiprone in Parkinson's Disease
David Devos
(1)
,
Julien Labreuche
(2)
,
Olivier Rascol
(3)
,
Jean-Christophe Corvol
(4)
,
Alain Duhamel
(2)
,
Pauline Guyon Delannoy
(5)
,
Werner Poewe
(6)
,
Yaroslau Compta
(7, 8, 9)
,
Nicola Pavese
(10)
,
Evžen Růžička
(11)
,
Petr Dušek
(11)
,
Bart Post
(12, 13)
,
Bastiaan R. Bloem
(12, 13)
,
Daniela Berg
(14)
,
Walter Maetzler
(14)
,
Markus Otto
(15)
,
Marie-Odile Habert
(16, 17)
,
Stéphane Lehericy
(4)
,
Joaquim Ferreira
(18)
,
Richard Dodel
(19)
,
Christine Tranchant
(20)
,
Alexandre Eusebio
(21, 22)
,
Stéphane Thobois
(23, 24)
,
Ana-Raquel Marques
(25)
,
Wassilios G. Meissner
(26, 27)
,
Fabienne Ory-Magne
(3)
,
Uwe Walter
(28)
,
Rob M.A. de Bie
(29)
,
Miguel Gago
(30)
,
Dolores Vilas
(31)
,
Jaime Kulisevsky
(32)
,
Cristina Januario
(33)
,
Miguel V.S. Coelho
(34)
,
Stefanie Behnke
(35)
,
Paul Worth
(36)
,
Klaus Seppi
(6)
,
Thavarak Ouk
(5, 37)
,
Camille Potey
(5, 37)
,
Céline Leclercq
(5, 37)
,
Romain Viard
(38)
,
Gregory Kuchcinski
(38)
,
Renaud Lopes
(38)
,
Jean-Pierre Pruvo
(39)
,
Pascal Pigny
(37)
,
Guillaume Garcon
(40)
,
Ophelie Simonin
(40)
,
Jessica Carpentier
(40)
,
Anne-Sophie Rolland
(1)
,
Dag Nyholm
(41)
,
Christoph Scherfler
(6)
,
Jean-François Mangin
(42, 4, 17)
,
Marie Chupin
(42, 4, 17)
,
Regis Bordet
(1)
,
David T. Dexter
,
Caroline Fradette
(43, 44)
,
Michael Spino
(43, 44)
,
Fernando Tricta
(43, 44)
,
Scott Ayton
(45)
,
Ashley I. Bush
(45)
,
Jean-Christophe Devedjian
(1)
,
James A. Duce
(46)
,
Ioav Cabantchik
(47)
,
Luc Defebvre
(48)
,
Dominique Deplanque
(49)
,
Caroline Moreau
(48)
1
Pôle Recherche -
Département de Pharmacologie Médicale [Lille]
2 LilNCog - Lille Neurosciences & Cognition - U 1172
3 CIC 1436 - Centre d'investigation clinique de Toulouse
4 ICM - Institut du Cerveau = Paris Brain Institute
5 CHU Lille - Direction de la recherche et de l’innovation
6 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
7 UB - Universitat de Barcelona
8 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
9 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
10 Newcastle University [Newcastle]
11 1. LF UK / 1st Faculty of Medicine - 1. lékařská fakulta, Univerzita Karlova [Praha, Česká republika] = First Faculty of Medicine, Charles University [Prague, Czech Republic]
12 Donders Institute for Brain, Cognition and Behaviour
13 Radboud University Medical Center [Nijmegen]
14 CAU - Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel
15 Universität Ulm - Ulm University [Ulm, Allemagne]
16 SU - Sorbonne Université
17 CATI - Centre d'Acquisition et de Traitement des Images [Paris] = CATI Multicenter Neuroimaging Platform
18 Universidade de Lisboa
19 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
20 FMTS - Fédération de Médecine Translationnelle de Strasbourg
21 INT - Institut de Neurosciences de la Timone
22 AMU - Aix Marseille Université
23 ISC-MJ - Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229
24 UCBL - Université Claude Bernard Lyon 1
25 UCA - Université Clermont Auvergne
26 University of Otago [Dunedin, Nouvelle-Zélande]
27 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
28 University of Rostock
29 Amsterdam UMC - Amsterdam University Medical Centers
30 Universidade do Minho = University of Minho [Braga]
31 GTPUH - Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain]
32 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
33 H.U.C. - Hospitais da Universidade de Coimbra
34 Hospital de Santa Maria [Lisboa]
35 UKS - Saarland University Hospital
36 Addenbrooke's Hospital
37 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
38 Services de neuroradiologie [Lille]
39 Service de neuroradiologie [Lille]
40 IMPECS - Impact de l'environnement chimique sur la santé humaine - ULR 4483
41 Uppsala University
42 BAOBAB - Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields
43 University of Toronto
44 Chiesi SAS
45 University of Melbourne
46 The Florey Institute of Neuroscience and Mental Health
47 HUJ - The Hebrew University of Jerusalem
48 Département de neurologie [Lille]
49 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
2 LilNCog - Lille Neurosciences & Cognition - U 1172
3 CIC 1436 - Centre d'investigation clinique de Toulouse
4 ICM - Institut du Cerveau = Paris Brain Institute
5 CHU Lille - Direction de la recherche et de l’innovation
6 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
7 UB - Universitat de Barcelona
8 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
9 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
10 Newcastle University [Newcastle]
11 1. LF UK / 1st Faculty of Medicine - 1. lékařská fakulta, Univerzita Karlova [Praha, Česká republika] = First Faculty of Medicine, Charles University [Prague, Czech Republic]
12 Donders Institute for Brain, Cognition and Behaviour
13 Radboud University Medical Center [Nijmegen]
14 CAU - Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel
15 Universität Ulm - Ulm University [Ulm, Allemagne]
16 SU - Sorbonne Université
17 CATI - Centre d'Acquisition et de Traitement des Images [Paris] = CATI Multicenter Neuroimaging Platform
18 Universidade de Lisboa
19 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
20 FMTS - Fédération de Médecine Translationnelle de Strasbourg
21 INT - Institut de Neurosciences de la Timone
22 AMU - Aix Marseille Université
23 ISC-MJ - Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229
24 UCBL - Université Claude Bernard Lyon 1
25 UCA - Université Clermont Auvergne
26 University of Otago [Dunedin, Nouvelle-Zélande]
27 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
28 University of Rostock
29 Amsterdam UMC - Amsterdam University Medical Centers
30 Universidade do Minho = University of Minho [Braga]
31 GTPUH - Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain]
32 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
33 H.U.C. - Hospitais da Universidade de Coimbra
34 Hospital de Santa Maria [Lisboa]
35 UKS - Saarland University Hospital
36 Addenbrooke's Hospital
37 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
38 Services de neuroradiologie [Lille]
39 Service de neuroradiologie [Lille]
40 IMPECS - Impact de l'environnement chimique sur la santé humaine - ULR 4483
41 Uppsala University
42 BAOBAB - Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields
43 University of Toronto
44 Chiesi SAS
45 University of Melbourne
46 The Florey Institute of Neuroscience and Mental Health
47 HUJ - The Hebrew University of Jerusalem
48 Département de neurologie [Lille]
49 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
David Devos
- Fonction : Auteur
- PersonId : 13309
- IdHAL : david-devos
- ORCID : 0000-0002-2417-799X
- IdRef : 091996309
Olivier Rascol
- Fonction : Auteur
- PersonId : 938353
- ORCID : 0000-0002-1410-6397
- IdRef : 084129980
Fabienne Ory-Magne
- Fonction : Auteur
- PersonId : 988022
- ORCID : 0000-0001-6179-4500
- IdRef : 061282650
David T. Dexter
- Fonction : Auteur
Résumé
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. opens in new tab.)