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Chapter 25 - Lessons learned: neuroprotective trials in Parkinson's disease

from Section IV - Clinical Trials in Parkinson's Diease: Lessons, Controversies and Challenges

Published online by Cambridge University Press:  05 March 2016

By
Isabelle Beaulieu-Boire  and
Anthony E. Lang
Edited by
Néstor Gálvez-Jiménez ,
Hubert H. Fernandez ,
Alberto J. Espay  and
Susan H. Fox
Néstor Gálvez-Jiménez
Affiliation:
Cleveland Clinic, Florida
Hubert H. Fernandez
Affiliation:
Cleveland Clinic, Ohio
Alberto J. Espay
Affiliation:
University of Cincinnati
Susan H. Fox
Affiliation:
Toronto Western Hospital
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Chapter
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Parkinson's Disease
Current and Future Therapeutics and Clinical Trials
 , pp. 265 - 279
Publisher: Cambridge University Press
Print publication year: 2016

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References

Lang, AE. Clinical trials of disease-modifying therapies for neurodegenerative diseases: the challenges and the future. Nat Med 2010; 16: 1223–6.CrossRefGoogle ScholarPubMed
Stocchi, F, Olanow, CW. Obstacles to the development of a neuroprotective therapy for Parkinson's disease. Mov Disord 2013; 28: 3–7.CrossRefGoogle Scholar
Olanow, CW, Kieburtz, K, Schapira, AHV. Why have we failed to achieve neuroprotection in Parkinson's disease? Ann Neurol 2009; 64 (Suppl. 2): S101–10.CrossRefGoogle Scholar
Hirsch, EC. How to improve neuroprotection in Parkinson's disease? Parkinsonism Relat Disord 2007; 13 (Suppl. 3): S332–5.CrossRefGoogle ScholarPubMed
D'Agostino, RB. The delayed-start study design. N Engl J Med 2009; 361: 1304–6.CrossRefGoogle ScholarPubMed
Cheng, HC, Ulane, CM, Burke, RE. Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 2010; 67: 715–25.CrossRefGoogle ScholarPubMed
Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000; 284: 1931–8.CrossRefGoogle Scholar
Fahn, S, Oakes, D, Shoulson, I, et al. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004; 351: 2498–508.Google ScholarPubMed
Whone, AL, Watts, RL, Stoessl, AJ, et al. Slower progression of Parkinson's disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003; 54: 93–101.CrossRefGoogle ScholarPubMed
Goetz, CG, Tilley, BC, Shaftman, SR, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008; 23: 2129–70.CrossRefGoogle ScholarPubMed
Hauser, RA, Auinger, P, Parkinson Study Group. Determination of minimal clinically important change in early and advanced Parkinson's disease. Mov Disord 2011; 26: 813–8.CrossRefGoogle ScholarPubMed
Richards, M, Marder, K, Cote, L, Mayeux, R. Interrater reliability of the Unified Parkinson's Disease Rating Scale motor examination. Mov Disord 1994; 9: 89–91.CrossRefGoogle ScholarPubMed
Goetz, CG, Leurgans, S, Raman, R, Parkinson Study Group. Placebo-associated improvements in motor function: Comparison of subjective and objective sections of the UPDRS in early Parkinson's disease. Mov Disord 2002; 17: 283–8.CrossRefGoogle ScholarPubMed
Parashos, SA, Swearingen, CJ, Biglan, KM, et al. Determinants of the timing of symptomatic treatment in early Parkinson disease: The National Institutes of Health Exploratory Trials in Parkinson Disease (NET-PD) Experience. Arch Neurol 2009; 66: 1099–104.CrossRefGoogle ScholarPubMed
Ravina, B, Camicioli, R, Como, PG, et al. The impact of depressive symptoms in early Parkinson disease. Neurology 2007; 69: 342–7.CrossRefGoogle ScholarPubMed
Marras, C, McDermott, MP, Marek, K, et al. Predictors of time to requiring dopaminergic treatment in 2 Parkinson's disease cohorts. Mov Disord 2011; 26: 608–13.CrossRefGoogle ScholarPubMed
Agarwal, PA, Stoessl, AJ. Biomarkers for trials of neuroprotection in Parkinson's disease. Mov Disord 2012; 28: 71–85.CrossRefGoogle ScholarPubMed
Pavese, N, Kiferle, L, Piccini, P. Neuroprotection and imaging studies in Parkinson's disease. Parkinsonism Relat Disord 2009; 15 (Suppl. 4): S33–7.CrossRefGoogle ScholarPubMed
Ravina, B, Eidelberg, D, Ahlskog, JE, et al. The role of radiotracer imaging in Parkinson disease. Neurology 2005; 64: 208–15.CrossRefGoogle ScholarPubMed
Snow, BJ, Tooyama, I, McGeer, EG, et al. Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels. Ann Neurol 1993; 34: 324–30.CrossRefGoogle ScholarPubMed
Nandhagopal, R, Kuramoto, L, Schulzer, M, et al. Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study. Brain. 2009; 132: 2970–9.CrossRefGoogle ScholarPubMed
Vingerhoets, FJ, Schulzer, M, Calne, DB, Snow, BJ. Which clinical sign of Parkinson's disease best reflects the nigrostriatal lesion? Ann Neurol 1997; 41: 58–64.CrossRefGoogle ScholarPubMed
Pirker, W. Correlation of dopamine transporter imaging with parkinsonian motor handicap: how close is it? Mov Disord 2003; 18: S43–51.CrossRefGoogle Scholar
Martin, WRW, Wieler, M, Stoessl, AJ, Schulzer, M. Dihydrotetrabenazine positron emission tomography imaging in early, untreated Parkinson's disease. Ann Neurol 2008; 63: 388–94.CrossRefGoogle ScholarPubMed
Morrish, PK. How valid is dopamine transporter imaging as a surrogate marker in research trials in Parkinson's disease? Mov Disord 2003; 18 (Suppl. 7): S63–70.CrossRefGoogle ScholarPubMed
Parkinson Study Group. A randomized controlled trial comparing pramipexole with levodopa in early Parkinson's disease: design and methods of the CALM-PD Study. Clin Neuropharmacol 2000; 23: 34–44.CrossRefGoogle Scholar
Winogrodzka, A, Booij, J, Wolters, EC. Disease-related and drug-induced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson's disease. Parkinsonism Relat Disord 2005; 11: 475–84.CrossRefGoogle ScholarPubMed
Eckert, T, Eidelberg, D. Neuroimaging and therapeutics in movement disorders. NeuroRx 2005; 2: 361–71.CrossRefGoogle ScholarPubMed
Eckert, T, Tang, C, Eidelberg, D. Assessment of the progression of Parkinson's disease: a metabolic network approach. Lancet Neurol 2007; 6: 926–32.CrossRefGoogle ScholarPubMed
Vaillancourt, DE, Spraker, MB, Prodoehl, J, et al. High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease. Neurology 2009; 72: 1378–84.CrossRefGoogle ScholarPubMed
Berg, D. Transcranial ultrasound as a risk marker for Parkinson's disease. Mov Disord 2009; 24 (Suppl. 2): S677–83.CrossRefGoogle ScholarPubMed
Sperling, RA, Aisen, PS, Beckett, LA, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011; 7: 280–92.CrossRefGoogle ScholarPubMed
Lang, AE, Melamed, E, Poewe, W, Rascol, O. Trial designs used to study neuroprotective therapy in Parkinson's disease. Mov Disord 2012; 28: 86–95.CrossRefGoogle ScholarPubMed
Olanow, CW, Rascol, O, Hauser, R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med 2009; 361: 1268–78.CrossRefGoogle ScholarPubMed
Clarke, CE. Are delayed-start design trials to show neuroprotection in Parkinson's disease fundamentally flawed? Mov Disord 2008; 23: 784–9.CrossRefGoogle ScholarPubMed
Ahlskog, JE, Uitti, RJ. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology 2010; 74: 1143–8.CrossRefGoogle ScholarPubMed
Schwid, SR, Cutter, GR. Futility studies: spending a little to save a lot. Neurology 2006; 66: 626–7.CrossRefGoogle ScholarPubMed
Bezard, E, Yue, Z, Kirik, D, Spillantini, MG. Animal models of Parkinson's disease: Limits and relevance to neuroprotection studies. Mov Disord 2012; 28: 61–70.CrossRefGoogle ScholarPubMed
Schober, A. Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP. Cell Tissue Res 2004; J318: 215–24.CrossRefGoogle Scholar
Luk, KC, Kehm, V, Carroll, J, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012; 338: 949–53.CrossRefGoogle ScholarPubMed
Olanow, CW, Brundin, P. Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? Mov Disord 2013; 28: 31–40.CrossRefGoogle ScholarPubMed
Lim, KL, Ng, CH. Genetic models of Parkinson disease. Biochim Biophys Acta 2009; 1792: 604–15.CrossRefGoogle ScholarPubMed
AlDakheel, A, Kalia, LV, Lang, AE. Pathogenesis-targeted, disease-modifying therapies in Parkinson disease. Neurotherapeutics 2013; 11: 6–23.CrossRefGoogle Scholar
Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson's disease. N Engl J Med 1989; 321: 1364–71.CrossRefGoogle Scholar
Olanow, CW, Hauser, RA, Gauger, L, et al. The effect of deprenyl and levodopa on the progression of Parkinson's disease. Ann Neurol 1995; 38: 771–7.CrossRefGoogle ScholarPubMed
Negrotti, A, Bizzarri, G, Calzetti, S. Long-term persistence of symptomatic effect of selegiline in Parkinson's disease. A two-months placebo-controlled withdrawal study. J Neural Transm 2001; 108: 215–19.CrossRefGoogle ScholarPubMed
Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002; 59: 1937–43.CrossRefGoogle Scholar
Clarke, CE, Patel, S, Ives, N, et al. Should treatment for Parkinson's disease start immediately on diagnosis or delayed until functional disability develops? Mov Disord 2011; 26: 1187–93.CrossRefGoogle ScholarPubMed
de la Fuente-Fernández, R, Schulzer, M, Mak, E, Sossi, V. Parkinsonism and related disorders. Parkinsonism Relat Disord 2010; 16: 365–9.CrossRefGoogle Scholar
Schwarzschild, MA. Rasagiline in Parkinson's disease. N Engl J Med 2010; 362: 658; author reply 658–9.Google ScholarPubMed
Fahn, S. Is levodopa toxic? Neurology 1996; 47 (Suppl. 3): S184–95.CrossRefGoogle Scholar
Jenner, PG, Brin, MF. Levodopa neurotoxicity: experimental studies versus clinical relevance. Neurology 1998; 50 (Suppl. 6): S39–48.CrossRefGoogle ScholarPubMed
Hauser, RA, Holford, NHG. Quantitative description of loss of clinical benefit following withdrawal of levodopa-carbidopa and bromocriptine in early Parkinson's disease. Mov Disord 2002; 17: 961–8.CrossRefGoogle ScholarPubMed
LEAP Study Protocol. Levodopa in early Parkinson's disease: the LEAP study. Availabe at: http://leapamc.nl/wp-content/uploads/2011-12-22-Onderzoeksprotocol.pdf.Google Scholar
Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002; 287: 1653–61.CrossRefGoogle Scholar
Parkinson Study Group, CALM Cohort Investigators. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol 2009; 66: 563–70.CrossRefGoogle Scholar
Schapira, AHV, Albrecht, S, Barone, P, et al. Rationale for delayed-start study of pramipexole in Parkinson's disease: the PROUD study. Mov Disord 2010; 25: 1627–32.CrossRefGoogle ScholarPubMed
Schapira, AHV, McDermott, MP, Barone, P, et al. Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial. Lancet Neurol 2013; 12: 747–55.CrossRefGoogle Scholar
NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 2006; 66: 664–71.CrossRefGoogle Scholar
NET-PD. Study News. Statement on the Termination of NET-PD LS-1 Study. Available at: http://parkinsontrial.ninds.nih.gov/netpd-LS1-study-termination.htm.Google Scholar
Parkinson Study Group PRECEPT Investigators. Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology 2007; 69: 1480–90.CrossRefGoogle Scholar
Olanow, CW, Schapira, AHV, LeWitt, PA, et al. TCH346 as a neuroprotective drug in Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol 2006; 5: 1013–20.CrossRefGoogle ScholarPubMed
Nutt, JG, Burchiel, KJ, Comella, CL, et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003; 60: 69–73.CrossRefGoogle ScholarPubMed
Lang, AE, Gill, S, Patel, NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006; 59: 459–66.CrossRefGoogle ScholarPubMed
Marks, WJ, Bartus, RT, Siffert, J, et al. Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol 2010; 9: 1164–72.CrossRefGoogle ScholarPubMed
Bartus, RT, Baumann, TL, Siffert, J, et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 2013; 80: 1698–701.CrossRefGoogle ScholarPubMed
PR Newswire. Ceregene reports data from Parkinson's disease phase 2b study. Available at: http://www.prnewswire.com/news-releases/ceregene-reports-data-from-parkinsons-disease-phase-2b-study-203803541.html.Google Scholar
Kordower, JH, Olanow, CW, Dodiya, HB, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. Brain 2013; 136: 2419–31.CrossRefGoogle ScholarPubMed
Liu, J, Wang, L, Zhan, SY, Xia, Y. Coenzyme Q10 for Parkinson's disease. Cochrane Database Syst Rev 2011; (12): CD008150.CrossRefGoogle ScholarPubMed
National Institute of Neurological Disorders and Stroke. Statement on Termination of QE3 Study. Available at: http://www.ninds.nih.gov/disorders/clinical_trials/CoQ10-Trial-Update.htm.Google Scholar
Snow, BJ, Rolfe, FL, Lockhart, MM, et al. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov Disord 2010; 25: 1670–4.CrossRefGoogle ScholarPubMed

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