Trial of Deferiprone in Parkinson's Disease
Por:
Devos, D, Labreuche, J, Rascol, O, Corvol, JC, Duhamel, A, Delannoy, PG, Poewe, W, Compta, Y, Pavese, N, Ruzicka, E, Dusek, P, Post, B, Bloem, BR, Berg, D, Maetzler, W, Otto, M, Habert, MO, Lehericy, S, Ferreira, J, Dodel, R, Tranchant, C, Eusebio, A, Thobois, S, Marques, AR, Meissner, WG, Ory-Magne, F, Walter, U, de Bie, RMA, Gago, M, Vilas, D, Kulisevsky, J, Januario, C, Coelho, MVS, Behnke, S, Worth, P, Seppi, K, Ouk, T, Potey, C, Leclercq, C, Viard, R, Kuchcinski, G, Lopes, R, Pruvo, JP, Pigny, P, Garcon, G, Simonin, O, Carpentier, J, Rolland, AS, Nyholm, D, Scherfler, C, Mangin, JF, Chupin, M, Bordet, R, Dexter, DT, Fradette, C, Spino, M, Tricta, F, Ayton, S, Bush, AI, Devedjian, JC, Duce, JA, Cabantchik, I, Defebvre, L, Deplanque, D and Moreau, C
Publicada:
1 dic 2022
Resumen:
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.
Filiaciones:
Devos, D:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Med Pharmacol,Team DVCD,INSERM,UMR, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Labreuche, J:
Univ Lille, CHU Lille, Dept Biostat, Lille, France
Rascol, O:
Univ Toulouse 3, Univ Hosp Toulouse, Clin Invest Ctr 1436, Dept Neurosci, Toulouse, France
Univ Toulouse 3, Univ Hosp Toulouse, Dept Clin Pharmacol, NS Park FCRIN Network & NeuroToul CoEN Ctr,INSERM, Toulouse, France
Corvol, JC:
Sorbonne Univ, AP HP, CNRS, INSERM, Paris, France
Hop La Pitie Salpetriere, Ctr Invest Clin Neurosci, Inst Cerveau & Moelle Epiniere ICM, Paris Brain Inst,Dept Neurol, Paris, France
Duhamel, A:
Univ Lille, CHU Lille, Dept Biostat, Lille, France
Delannoy, PG:
CHU Lille, Direct Rech & Innovat, Lille, France
Poewe, W:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Compta, Y:
Univ Barcelona, Hosp Clin Barcelona, Inst Invest Biomed August Pi & Sunyer,Parkinsons, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Pavese, N:
Newcastle Univ, Clin Ageing Res Unit, Newcastle Upon Tyne, Tyne & Wear, England
Ruzicka, E:
Charles Univ Prague, Dept Neurol, Prague, Czech Republic
Charles Univ Prague, Fac Med 1, Ctr Clin Neurosci, Prague, Czech Republic
Gen Univ Hosp, Prague, Czech Republic
Dusek, P:
Charles Univ Prague, Dept Neurol, Prague, Czech Republic
Charles Univ Prague, Fac Med 1, Ctr Clin Neurosci, Prague, Czech Republic
Gen Univ Hosp, Prague, Czech Republic
Post, B:
Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands
Bloem, BR:
Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands
Berg, D:
Christian Albrechts Univ Kiel, Dept Neurol, Kiel, Germany
Maetzler, W:
Christian Albrechts Univ Kiel, Dept Neurol, Kiel, Germany
Otto, M:
Univ Clin, Dept Neurol, Ulm, Germany
Habert, MO:
Sorbonne Univ, CNRS, INSERM, Lab Imagerie Biomed, Paris, France
Hop La Pitie Salpetriere, AP HP, Dept Nucl Med, Paris, France
Sorbonne Univ, CEA, Ctr Acquisit & Traitement Images, ICM,CNRS,INSERM,APHP, Paris, France
Lehericy, S:
Sorbonne Univ, Hop Pitie Salpetriere, AP HP,INSERM,Unite 1127,Dept Neuroradiol, Paris Brain Inst ICM,Ctr Neuroimaging Res,CNRS 72, Paris, France
Ferreira, J:
Univ Lisbon, Fac Arquitetura, Ctr Invest Arquitetura Urbanismo & Design, Lisbon, Portugal
Dodel, R:
Univ Duisburg Essen, Dept Geriatr Med, Essen, Germany
Tranchant, C:
Univ Strasbourg, Strasbourg Univ Hosp, Federat Med Translat Strasbourg, Dept Neurol,NS Park FCRIN Network, Strasbourg, France
Eusebio, A:
Timone Univ Hosp, AP HM, Dept Neurol & Movement Disorders, Marseille, France
Aix Marseille Univ, CNRS, Inst Neurosci Timone, UMR 7289, Marseille, France
Thobois, S:
Univ Lyon, Hosp Civils Lyon, Hop Neurolog Pierre Wertheimer, CNRS,UMR 5229,Serv Neurol,Ctr Expert Parkinson NS, Lyon, France
Marques, AR:
Univ Clermont Auvergne, Clermont Ferrand Univ Hosp, Dept Neurol, EA7280, Clermont Ferrand, France
Meissner, WG:
Univ Bordeaux, CHU Bordeaux, Serv Neurol Malad Neurodegenerat, Inst Malad Neurodegenerat IMN Clin,CNRS,IMN,UMR 5, Bordeaux, France
Univ Otago, Dept Med, Christchurch Campus, Christchurch, New Zealand
New Zealand Brain Res Inst, Christchurch, New Zealand
Ory-Magne, F:
Univ Toulouse 3, Univ Hosp Toulouse, Clin Invest Ctr 1436, Dept Neurosci, Toulouse, France
Univ Toulouse 3, Univ Hosp Toulouse, Dept Clin Pharmacol, NS Park FCRIN Network & NeuroToul CoEN Ctr,INSERM, Toulouse, France
Walter, U:
Rostock Univ, Med Ctr, Dept Neurol, Rostock, Germany
German Ctr Neurodegenerat Dis, Res Site Rostock, Rostock, Germany
de Bie, RMA:
Univ Amsterdam, Dept Neurol, Amsterdam UMC Locat, Amsterdam, Netherlands
Amsterdam Neurosci, Neurodegenerat, Amsterdam, Netherlands
Gago, M:
Hosp Senhora Oliveira, Dept Neurol, Guimaraes, Portugal
Univ Minho, Sch Med, Life & Hlth Sci Res Inst, Braga, Portugal
:
Hosp Badalona Germans Trias & Pujol, Movement Disorders Unit, Badalona, Spain
Kulisevsky, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, St Pau Biomed Res Inst, Movement Disorders Unit,Neurol Dept,Dept Med, Barcelona, Spain
CIBERNED, Barcelona, Spain
Januario, C:
Hop Univ Coimbra, Dept Neurol, Coimbra, Portugal
Coelho, MVS:
Hosp Santa Maria, Lisbon, Portugal
Behnke, S:
Univ Hosp Saarland, Homburg, Germany
Worth, P:
Addenbrookes Hosp, Cambridge, England
Seppi, K:
Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria
Ouk, T:
CHU Lille, Direct Rech & Innovat, Lille, France
CHU Lille, Vigilance Essais Clin & Serv Pharmacol, Lille, France
Potey, C:
CHU Lille, Direct Rech & Innovat, Lille, France
CHU Lille, Vigilance Essais Clin & Serv Pharmacol, Lille, France
Leclercq, C:
CHU Lille, Direct Rech & Innovat, Lille, France
CHU Lille, Vigilance Essais Clin & Serv Pharmacol, Lille, France
Viard, R:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Neuroradiol,Team DVCD,INSERM,UMRS, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Kuchcinski, G:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Neuroradiol,Team DVCD,INSERM,UMRS, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Lopes, R:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Neuroradiol,Team DVCD,INSERM,UMRS, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Pruvo, JP:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Neuroradiol,Team DVCD,INSERM,UMRS, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Pigny, P:
CHU Lille, Ctr Biol Pathol, Lab Biochim Hormonol, Lille, France
Garcon, G:
Univ Lille, CHU Lille, Inst Pasteur Lille, Impact Environm Chim Sante Humaine ULR4483, Lille, France
Simonin, O:
Univ Lille, CHU Lille, Inst Pasteur Lille, Impact Environm Chim Sante Humaine ULR4483, Lille, France
Carpentier, J:
Univ Lille, CHU Lille, Inst Pasteur Lille, Impact Environm Chim Sante Humaine ULR4483, Lille, France
Rolland, AS:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Med Pharmacol,Team DVCD,INSERM,UMR, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Nyholm, D:
Uppsala Univ, Neurol, Dept Med Sci, Uppsala, Sweden
Mangin, JF:
Sorbonne Univ, CEA, Ctr Acquisit & Traitement Images, ICM,CNRS,INSERM,APHP, Paris, France
Sorbonne Univ, INSERM, Unite 1127, ICM,CNRS,UMR 7725, Paris, France
Univ Paris Saclay, CEA, CNRS, NeuroSpin,Baobab, Gif Sur Yvette, France
Chupin, M:
Sorbonne Univ, CEA, Ctr Acquisit & Traitement Images, ICM,CNRS,INSERM,APHP, Paris, France
Sorbonne Univ, INSERM, Unite 1127, ICM,CNRS,UMR 7725, Paris, France
Univ Paris Saclay, CEA, CNRS, NeuroSpin,Baobab, Gif Sur Yvette, France
Bordet, R:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Med Pharmacol,Team DVCD,INSERM,UMR, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Dexter, DT:
Parkinsons UK, London, England
Fradette, C:
Univ Toronto, ApoPharma, Leslie Dan Fac Pharm, Toronto, ON, Canada
Chiesi Canada, Toronto, ON, Canada
Spino, M:
Univ Toronto, ApoPharma, Leslie Dan Fac Pharm, Toronto, ON, Canada
Chiesi Canada, Toronto, ON, Canada
Tricta, F:
Univ Toronto, ApoPharma, Leslie Dan Fac Pharm, Toronto, ON, Canada
Chiesi Canada, Toronto, ON, Canada
Ayton, S:
Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne Dementia Res Ctr, Parkville, Vic, Australia
Bush, AI:
Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne Dementia Res Ctr, Parkville, Vic, Australia
Devedjian, JC:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Med Pharmacol,Team DVCD,INSERM,UMR, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Duce, JA:
Univ Cambridge, Cambridge Biomed Campus, ALBORADA Drug Discovery Inst, Cambridge, England
Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Melbourne Dementia Res Ctr, Parkville, Vic, Australia
Cabantchik, I:
Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, Jerusalem, Israel
Defebvre, L:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Neurol,Team DVCD,INSERM,UMRS 1172, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
Deplanque, D:
Univ Lille, CHU Lille, INSERM, Unite Degenerat & Vasc Cognit Disorders 1172, Lille, France
Moreau, C:
Univ Lille, Network Ctr Excellence Neurodegenerat CoEN Ctr,De, CHU Lille,Dept Neurol,Team DVCD,INSERM,UMRS 1172, Lille Ctr Excellence Neurodegenerat Disorders LiC, Lille, France
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