Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease

作者：Alan Whone, Matthias Luz, M Boca, Max Woolley, Lucy Mooney, Sonali Dharia, Jack Broadfoot, David Cronin, Christian Schroers, Neil U. Barua, Lara Longpre, Corlane Barclay, Chris Boiko, Greg A. Johnson, H.C. Fibiger, Rob Harrison, Owen T. Lewis, Gemma Pritchard, Mike Howell, Charlie Irving, David W. Johnson, Suk Kinch, Christopher Marshall, Andrew D. Lawrence, Stephan Blinder, Vesna Sossi, A. Jon Stoessl, Paul Skinner, Erich Mohr, Steven S. Gill · 发表于：Brain · 年份：2019 · DOI：10.1093/brain/awz023 · 被引用次数：288 · 研究领域：Nerve injury and regeneration、Parkinson's Disease Mechanisms and Treatments、Autism Spectrum Disorder Research

We investigated the effects of glial cell line-derived neurotrophic factor (GDNF) in Parkinson's disease, using intermittent intraputamenal convection-enhanced delivery via a skull-mounted transcutaneous port as a novel administration paradigm to potentially afford putamen-wide therapeutic delivery. This was a single-centre, randomized, double-blind, placebo-controlled trial. Patients were 35-75 years old, had motor symptoms for 5 or more years, and presented with moderate disease severity in the OFF state [Hoehn and Yahr stage 2-3 and Unified Parkinson's Disease Rating Scale motor score (part III) (UPDRS-III) between 25 and 45] and motor fluctuations. Drug delivery devices were implanted and putamenal volume coverage was required to exceed a predefined threshold at a test infusion prior to randomization. Six pilot stage patients (randomization 2:1) and 35 primary stage patients (randomization 1:1) received bilateral intraputamenal infusions of GDNF (120 µg per putamen) or placebo every 4 weeks for 40 weeks. Efficacy analyses were based on the intention-to-treat principle and included all patients randomized. The primary outcome was the percentage change from baseline to Week 40 in the OFF state (UPDRS-III). The primary analysis was limited to primary stage patients, while further analyses included all patients from both study stages. The mean OFF state UPDRS motor score decreased by 17.3 ± 17.6% in the active group and 11.8 ± 15.8% in the placebo group (least squares mean di...