Trial of Deferiprone in Parkinson's Disease.
Humans
Deferiprone
/ administration & dosage
Iron
/ analysis
Levodopa
/ therapeutic use
Neutropenia
/ chemically induced
Parkinson Disease
/ drug therapy
Iron Chelating Agents
/ administration & dosage
Substantia Nigra
/ chemistry
Disease Progression
Double-Blind Method
Administration, Oral
Brain
/ diagnostic imaging
Brain Chemistry
Dopamine Agents
/ administration & dosage
Antiparkinson Agents
/ administration & dosage
Journal
The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562
Informations de publication
Date de publication:
01 12 2022
01 12 2022
Historique:
entrez:
30
11
2022
pubmed:
1
12
2022
medline:
3
12
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.).
Sections du 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.).
Identifiants
pubmed: 36449420
doi: 10.1056/NEJMoa2209254
doi:
Substances chimiques
Deferiprone
2BTY8KH53L
Iron
E1UOL152H7
Levodopa
46627O600J
Iron Chelating Agents
0
Dopamine Agents
0
Antiparkinson Agents
0
Banques de données
ClinicalTrials.gov
['NCT02655315']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2045-2055Subventions
Organisme : Medical Research Council
ID : MR/S005048/1
Pays : United Kingdom
Investigateurs
Luc Defebvre
(L)
Olivier Rascol
(O)
Christine Tranchant
(C)
Alexandre Eusebio
(A)
Stéphane Thobois
(S)
Jean-Christophe Corvol
(JC)
Franck Durif
(F)
Wassilos Meissner
(W)
Compta Yaroslau
(C)
Dolores Vilas
(D)
Jaime Kulisevsky
(J)
Werner Poewe
(W)
Evzen Ruzicka
(E)
Miguel Gago
(M)
Cristina Januario
(C)
Miguel Vilhena Soares Coelho
(M)
Daniela Berg
(D)
Stefanie Behnke
(S)
Uwe Walter
(U)
Paul Worth
(P)
Nicola Pavese
(N)
Bart Post
(B)
Rob M A de Bie
(RMA)
Giovanni Abbruzzese
(G)
Bertrand Accart
(B)
Marie-Anne Allain
(MA)
Mathieu Anheim
(M)
Diego Ardigo
(D)
Ignacio Aracil-Bolaños
(I)
Paul Baba
(P)
Martijn Bakker
(M)
Monika Balzer-Geldsetzer
(M)
Núria Bargalló
(N)
Paolo Barone
(P)
Sandra Basenau
(S)
Vincent Beliveau
(V)
Eve Benchetrit
(E)
Laura Best
(L)
Bas Bloem
(B)
Robin Bonicel
(R)
T Boraud
(T)
Regis Bordet
(R)
Raquel Bouca
(R)
Frédéric Bourdain
(F)
Jimena Bouzas
(J)
Christine Brefel-Courbon
(C)
Michael Bubenheim
(M)
David Burn
(D)
Ashley I Bush
(AI)
Ioav Cabantchik
(I)
Fabienne Calvas
(F)
Ana Cámara
(A)
Antonia Campolongo
(A)
Nicolas Carrière
(N)
Véronique Chaigneau
(V)
Collin Matthieu
(C)
Yaroslau Compta
(Y)
John Connelly
(J)
Florence Cormier-Dequaire
(F)
Amy Cranston
(A)
Rory Dean
(R)
Roberto De Marzi
(R)
Bertrand Degos
(B)
Jacques Demotes
(J)
Estelle Dellapina
(E)
Dominique Deplanque
(D)
Jean-Christophe Devedjian
(JC)
David Devos
(D)
David Dexter
(D)
Richard Dodel
(R)
Carole Dongmo
(C)
James Duce
(J)
Alain Duhamel
(A)
Julia Dupouy
(J)
Petr Dusek
(P)
Fouzia El Mountassir
(F)
Frédéric Eyvrard
(F)
Manel Fernández
(M)
Joaquim Ferreira
(J)
Gian Luca Forni
(GL)
Victoria Foster
(V)
Alexandra Foubert-Samier
(A)
Caroline Fradette
(C)
Laëtitia Fréville
(L)
Monique Galitzky
(M)
Cecile Gaudebout
(C)
Patrick Gelé
(P)
Nir Giladi
(N)
David Grabli
(D)
Franck Gleixner
(F)
Guillaume Grolez
(G)
Pauline Guyon
(P)
Marie-Odile Habert
(MO)
Estelle Harroch
(E)
Andreas Hartmann
(A)
Denise Hirsch
(D)
Michael Hisbergues
(M)
Markus A Hobert
(MA)
Franziska Hopfner
(F)
Camille Jurado
(C)
Andreas Kaiser
(A)
Gill Keen
(G)
Seppi Klaus
(S)
Nadège Kouassi
(N)
Julien Labreuch
(J)
Lucette Lacomblez
(L)
Ouhaid Lagha Boukbiza
(O)
Barbara Lanthaler
(B)
Gilles Lechatellier
(G)
Nadine Le Forestier
(N)
Fred Lehmann
(F)
Teresa Lloret
(T)
J Le Naour
(J)
Benjamin Le Toullec
(B)
Maxime Locatelli
(M)
Matthias Löhle
(M)
F Lomeña
(F)
Nadine Longato
(N)
Ulf Lützen
(U)
Ann McNichol
(A)
Corina Maetzler
(C)
Walter Maetzler
(W)
Philipp Mahlknecht
(P)
Graziella Mangone
(G)
Juan Marín-Lahoz
(J)
Louise-Laure Mariani
(LL)
Ana Marques
(A)
Mihaela Matei
(M)
Löhle Matthias
(L)
Emilie Maucourt Bacchi
(E)
Wassilios Meissner
(W)
Amelie Michon
(A)
Caroline Moreau
(C)
Nardo Nardocci
(N)
Florence Nosal
(F)
Dag Nyholm
(D)
Patrick Oeckl
(P)
Irena Oravska
(I)
Fabienne Ory
(F)
Markus Otto
(M)
Thavarak Ouk
(T)
Javier Pagonabarraga
(J)
Berta Pascual-Sedano
(B)
Marina Peball
(M)
Clélie Phillips
(C)
Fanny Pineau
(F)
Lluís Planellas
(L)
Chiesi Pop-Ilieva
(C)
Aurélie Rabier
(A)
D Olivier
(D)
Christian Riedel
(C)
Maura Rodrigues
(M)
Isabelle Roullet-Solignac
(I)
Christian Rose
(C)
Anna Rozova
(A)
Evžen Růžička
(E)
Alexandra Salis
(A)
Eva Schäffer
(E)
Christoph Scherfler
(C)
Natalia Schiefermeier
(N)
Klaus Seppi
(K)
Delphine Smagghe
(D)
Tânia Silva
(T)
Pedro Silva
(P)
Julie Socha
(J)
Corinne Souyris
(C)
Umberto Spampinato
(U)
Michael Spino
(M)
Alison Steel
(A)
Bajaj Sweta
(B)
Claire Thalamas
(C)
Danaila Teodor
(D)
Anna Teresa
(A)
François Tison
(F)
Eduardo Tolosa
(E)
Fernando Tricta
(F)
Gianluca Trifirò Trifirò
(G)
Marie Vidailhet
(M)
Yi Wang
(Y)
Mario Werkmann
(M)
Rezzak Yilmas
(R)
Hana You
(H)
Kirsten Zeuner
(K)
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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